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Abstract:

The present application relates to novel sulfonamidw- or
sulfoximine-substituted 1,4-diaryldihydropyrimidin-2-one derivatives, to
processes for their preparation, to their use alone or in combination for
the treatment and/or prevention of diseases and also to their use for
preparing medicaments for the treatment and/or prevention of diseases, in
particular for the treatment and/or prevention of disorders of the lung
and the cardiovascular system.

Claims:

1. A compound of the formula (I) ##STR00105## in which Z represents a
sulfonamide grouping of the formula ##STR00106## or represents a
sulfoximine grouping of the formula ##STR00107## in which * denotes
the point of attachment to the phenyl ring, RZ1 represents hydrogen,
or represents (C1-C6)-alkyl which may be substituted by
hydroxyl, (C1-C4)-alkoxy, amino, mono- or
di-(C1-C4)-alkylamino and up to three times by fluorine,
RZ2 represents hydrogen, (C3-C6)-cycloalkyl, 4- to
6-membered heterocyclyl or 5- or 6-membered heteroaryl or represents
(C1-C6)-alkyl which may be substituted by hydroxyl,
(C1-C4)-alkoxy, amino, mono- or
di-(C1-C4)-alkylamino, (C1-C4)-alkylcarbonylamino,
(C1-C4)-alkoxycarbonylamino, (C1-C4)-alkylsulfinyl,
(C1-C4)-alkylsulfonyl, (C3-C6)-cycloalkyl, phenyl, 4-
to 6-membered heterocyclyl, 5- or 6-membered heteroaryl or a group of the
formula --C(═O)--NRZ5RZ6 and up to three times by fluorine,
where the alkoxy substituent mentioned for its part may be substituted up
to three times by fluorine, and where the heterocyclyl groups mentioned
may be substituted up to two times by identical or different substituents
from the group consisting of fluorine, (C1-C4)-alkyl, oxo,
hydroxyl, (C1-C4)-alkoxy, amino, mono- and
di-(C1-C4)-alkylamino and the phenyl group mentioned and the
heteroaryl groups mentioned may be substituted up to two times by
identical or different substituents from the group consisting of
fluorine, chlorine, cyano, (C1-C4)-alkyl, difluoromethyl,
trifluoromethyl and (C1-C4)-alkoxy, and where RZ5 and
RZ6 are identical or different and independently of one another
represent hydrogen or (C1-C4)-alkyl or RZ5 and RZ6
together with the nitrogen atom to which they are attached form a 4- to
6-membered aza heterocycle which may contain a further ring heteroatom
from the group consisting of N, O and S and may be substituted by
(C1-C4)-alkyl, oxo, hydroxyl, (C1-C4)-alkoxy, amino,
mono- or di-(C1-C4)-alkylamino, or RZ1 and RZ2
together with the nitrogen atom to which they are attached form a 4- to
10-membered aza heterocycle which may contain a further ring heteroatom
from the group consisting of N, O and S and may be substituted up to two
times by identical or different substituents from the group consisting of
fluorine, (C1-C4)-alkyl, oxo, hydroxyl,
(C1-C4)-alkoxy, amino, mono- and
di-(C1-C4)-alkylamino, RZ3 represents
(C1-C6)-alkyl which may be substituted by
(C3-C6)-cycloalkyl or up to three times by fluorine, or
represents phenyl which may be substituted up to two times by identical
or different substituents from the group consisting of fluorine,
chlorine, cyano, (C1-C4)-alkyl, difluoromethyl and
trifluoromethyl, or represents (C3-C6)-cycloalkyl, and RZ4
represents hydrogen, (C1-C4)-alkyl or
(C3-C6)-cycloalkyl, R1 represents cyano or acetyl, R2
represents hydrogen, represents (C1-C4)-alkyl or
(C1-C4)-alkylsulfonyl which may be substituted up to three
times by fluorine, or represents a group of the formula
--CH2--C(═O)--NH--R4 in which R4 represents hydrogen,
represents (C1-C4)-alkyl which may be substituted by
(C3-C6)-cycloalkyl or up to three times by fluorine, or
represents (C3-C6)-cycloalkyl, and R3 represents hydrogen,
fluorine or chlorine, or a salt, a solvate or a solvate of a salt
thereof.

2. The compound of claim 1 in which Z represents a sulfonamide grouping
of the formula ##STR00108## or represents a sulfoximine grouping of
the formula ##STR00109## in which * denotes the point of attachment to
the phenyl ring, RZ1 represents hydrogen or represents
(C1-C4)-alkyl which may be substituted by hydroxyl, methoxy or
ethoxy, RZ2 represents hydrogen, (C3-C6)-cycloalkyl, 5- or
6-membered heterocyclyl or 5- or 6-membered heteroaryl or represents
(C1-C4)-alkyl which may be substituted by hydroxyl,
(C1-C4)-alkoxy, amino, mono- or
di-(C1-C4)-alkylamino, (C1-C4)-alkylcarbonylamino,
(C1-C4)-alkoxycarbonylamino, (C1-C4)-alkylsulfinyl,
(C1-C4)-alkylsulfonyl, (C3-C6)-cycloalkyl, phenyl, 5-
or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or a group of the
formula --C(═O)--NRZ5RZ6 and up to three times by fluorine,
where the alkoxy substituent mentioned for its part may be substituted up
to three times by fluorine, and where the heterocyclyl groups mentioned
may be substituted up to two times by identical or different substituents
from the group consisting of (C1-C4)-alkyl, oxo, hydroxyl and
(C1-C4)-alkoxy and the phenyl group mentioned and the
heteroaryl groups mentioned may be substituted up to two times by
identical or different substituents from the group consisting of
fluorine, chlorine, cyano, (C1-C4)-alkyl, tri-fluoromethyl and
(C1-C4)-alkoxy, and where RZ5 and RZ6 are identical
or different and independently of one another represent hydrogen or
(C1-C4)-alkyl or RZ5 and RZ6 together with the
nitrogen atom to which they are attached form a 5- or 6-membered aza
heterocycle which may contain a further ring heteroatom from the group
consisting of N and O and may be substituted by (C1-C4)-alkyl,
oxo, hydroxyl or (C1-C4)-alkoxy, or RZ1 and RZ2
together with the nitrogen atom to which they are attached form a 5- to
10-membered aza heterocycle which may contain a further ring heteroatom
from the group consisting of N and O and may be substituted up to two
times by identical or different substituents from the group consisting of
(C1-C4)-alkyl, oxo, hydroxyl and (C1-C4)-alkoxy,
RZ3 represents (C1-C4)-alkyl which may be substituted by
(C3-C6)-cycloalkyl or up to three times by fluorine, or
represents phenyl which may be substituted up to two times by identical
or different substituents from the group consisting of fluorine,
chlorine, cyano, methyl and tri-fluoromethyl, or represents
(C3-C6)-cycloalkyl, and RZ4 represents hydrogen, methyl or
cyclopropyl, R1 represents cyano, R2 represents hydrogen,
(C1-C4)-alkyl or (C1-C4)-alkylsulfonyl, each of which
may be substituted up to three times by fluorine, or represents a group
of the formula --CH2--C(═O)--NH--R4 in which R4
represents hydrogen, methyl, cyclopropyl or cyclopropylmethyl, and
R3 represents hydrogen or fluorine, or a salt, a solvate or a
solvate of a salt thereof.

3. The compound of claim 1 in which Z represents a sulfonamide grouping
of the formula ##STR00110## in which * denotes the point of attachment
to the phenyl ring, RZ1 represents hydrogen, methyl or
2-hydroxyethyl, RZ2 represents hydrogen, cyclopropyl, 5- or
6-membered heterocyclyl or 5- or 6-membered heteroaryl or represents
(C1-C4)-alkyl which may be substituted by hydroxyl, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino,
acetylamino, cyclopropyl, 5- or 6-membered heterocyclyl or a group of the
formula --C(═O)--NRZ5RZ6, where methoxy and ethoxy
substituents mentioned for their part may be substituted up to three
times by fluorine, and where the heterocyclyl groups mentioned may be
substituted up to two times by identical or different substituents from
the group consisting of methyl, ethyl, oxo, hydroxyl, methoxy and ethoxy
and the heteroaryl group mentioned may be substituted up to two times by
identical or different substituents from the group consisting of
fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy and
ethoxy, and where RZ5 and RZ6 independently of one another
represent hydrogen or methyl or together with the nitrogen atom to which
they are attached form a pyrrolidine, piperidine or morpholine ring, or
RZ1 and RZ2 together with the nitrogen atom to which they are
attached form a pyrrolidine, piperidine or morpholine ring, R1
represents cyano, R2 represents hydrogen, methyl, methylsulfonyl or
the group of the formula --CH2--C(═O)--NH2, and R3
represents hydrogen, or a salt, a solvate or a solvate of a salt thereof.

4. The compound of claim 1 in which Z represents a sulfoximine grouping
of the formula ##STR00111## in which * denotes the point of attachment
to the phenyl ring and RZ3 represents (C1-C4)-alkyl which
may be substituted by cyclopropyl or up to three times by fluorine, or
represents cyclopropyl, R1 represents cyano, R2 represents
hydrogen, methyl, methylsulfonyl or the group of the formula
--CH2--C(═O)--NH2, and R3 represents hydrogen, or a
salt, a solvate or a solvate of a salt thereof.

5. The compound of claim 1 in which Z represents a sulfonamide grouping
of the formula ##STR00112## in which * denotes the point of attachment
to the phenyl ring and RZ2 represents hydrogen, methyl or the group
of the formula --CH2--C(═O)--NH2, R1 represents cyano,
R2 represents hydrogen, methyl or methylsulfonyl, and R3
represents hydrogen, or a salt, a solvate or a solvate of a salt thereof.

6. The compound of claim 1 in which Z represents a sulfoximine grouping
of the formula ##STR00113## in which * denotes the point of attachment
to the phenyl ring, R1 represents cyano, R2 represents
hydrogen, methyl or methylsulfonyl, and R3 represents hydrogen, or a
salt, a solvate or a solvate of a salt thereof.

7. A process for preparing a compound of the formula (I) of claim 1, in
which Z represents a sulfonamide grouping of the formula ##STR00114##
in which * denotes the point of attachment to the phenyl ring and
RZ1 and RZ2 have the meanings given in claim 1, comprising:
converting an aniline derivative of the formula (II) ##STR00115## in
which R1, R2 and R3 have the meanings given in of claim 1,
with sodium nitrite and hydrochloric acid into the corresponding
diazonium salt and reacting the diazonium salt in a one-pot reaction with
sulfur dioxide in the presence of copper(I) chloride to give a sulfonyl
chloride of the formula (III) ##STR00116## in which R1, R2
and R3 have the meanings given above, reacting the sulfonyl chloride
of the formula (III) with an amine of the formula (IV) ##STR00117## in
which RZ1 and RZ2 have the meanings given in any of claims 1,
2, 3 and 5, if appropriate in the presence of an auxiliary base, to give
the sulfonamide of the formula (I-A) ##STR00118## in which R1,
R2, R3, RZ1 and RZ2 have the meanings given above,
and optionally, separating compounds of the formula (I-A) obtained in
this manner by methods known to the person skilled in the art into their
enantiomers and/or diastereomers and/or converted with the appropriate
(i) solvents and/or (ii) bases or acids into their solvates, salts and/or
solvates of the salts.

8. A process for preparing a compounds of the formula (I) of claim 1, in
which Z represents a sulfoximine grouping of the formula ##STR00119##
in which * denotes the point of attachment to the phenyl ring and
RZ3 has the meaning given in any of claims 1, 2, 4 and 6,
comprising, oxidizing a phenyl thioether derivative of the formula (V)
##STR00120## in which R1, R2, R3 and RZ3 have the
meanings given in any of claims 1, 2, 4 and 6, with hydrogen peroxide, a
peracid or a periodate to give the sulfoxide of the formula (VI)
##STR00121## in which R1, R2, R3 and RZ3 have the
meanings given above, converting the sulfoxide of formula (VI) with
2,2,2-trifluoroacetamide and (diacetoxyiodo)benzene in the presence of
dimeric rhodium(II) acetate as catalyst and magnesium oxide as base into
an N-acylsulfoximine of the formula (VII) ##STR00122## in which
R1, R2, R3 and RZ3 have the meanings given above, and
removing the trifluoroacetyl group in the N-acylsulfoximine of the
formula (VII) under basic conditions to give the sulfoximine of the
formula (I-B) ##STR00123## in which R1, R2, R3 and
RZ3 have the meanings given above, and optionally separating the
compounds of the formula (I-B) obtained in this manner by methods known
to the person skilled in the art into their enantiomers and/or
diastereomers and/or converted with the appropriate (i) solvents and/or
(ii) bases or acids into their solvates, salts and/or solvates of the
salts.

9. (canceled)

10. (canceled)

11. (canceled)

12. A pharmaceutical composition comprising a compound of claim 1 in
combination with one or more inert non-toxic pharmaceutically acceptable
auxiliaries.

13. The pharmaceutical composition of claim 12, further comprising at
least one further active compounds selected from the group of the kinase
inhibitors, matrix metalloprotease inhibitors, stimulators and activators
of soluble guanylate cyclase, prostacyclin analogs, endothelin receptor
antagonists, phosphodiesterase inhibitors, beta-adrenergic receptor
agonists, anticholinergics and glucocorticoids.

14. (canceled)

15. A method for the treatment and/or prevention of pulmonary arterial
hypertension (PAH) and other forms of pulmonary hypertension (PH), of
chronic-obstructive pulmonary diseases (COPD), of acute lung injury
(ALI), of acute respiratory distress syndrome (ARDS), of pulmonary
emphysema, of alpha-1 antitrypsin deficiency (AATD) and of cystic
fibrosis (CF) comprising administering an effective amount of at least
one compound of claim 1 to a human or animal in need thereof.

16. A method for the treatment and/or prevention of pulmonary arterial
hypertension (PAH) and other forms of pulmonary hypertension (PH), of
chronic-obstructive pulmonary diseases (COPD), of acute lung injury
(ALI), of acute respiratory distress syndrome (ARDS), of pulmonary
emphysema, of alpha-1 antitrypsin deficiency (AATD) and of cystic
fibrosis (CF) comprising administering an effective amount of at least
one pharmaceutical composition of claim 12 to a human or animal in need
thereof.

Description:

[0001] The present application relates to novel sulfonamide- or
sulfoximine-substituted 1,4-diaryldihydropyrimidin-2-one derivatives, to
processes for their preparation, to their use alone or in combination for
the treatment and/or prevention of diseases and also to their use for
preparing medicaments for the treatment and/or prevention of diseases, in
particular for the treatment and/or prevention of disorders of the lung
and the cardiovascular system.

[0002] Human leukocyte elastase (HLE, EC 3.4.21.37), also called human
neutrophil elastase (HNE, hNE), belongs to the family of the serine
proteases. The proteolytic enzyme is found in the azurophilic granules of
polymorphonuclear leukocytes (PMN leukocytes). Intracellular elastase
performs an important function in defense against pathogens by breaking
down the foreign particles taken by phagocytosis. Activated neutrophilic
cells release the HNE from the granules into the extracellular space
(extracellular HNE), with some of the released HNE remaining on the
outside of the neutrophilic cell membrane (membrane-associated HNE). The
highly active enzyme is able to break down a large number of connective
tissue proteins, for example the proteins elastin, collagen and
fibronectin. Elastin occurs in high concentrations in all tissue types
showing high elasticity, for example in the lung and the arteries. HNE is
involved in the tissue breakdown and transformation (tissue remodeling)
associated with a large number of pathological processes (for example
tissue injuries). HNE is also an important modulator of inflammatory
processes. HNE induces for example increased interleukin-8 (IL-8) gene
expression.

[0003] Accordingly, it is presumed that HNE plays an important role in
many disorders, injuries and pathological changes whose formation and/or
progression are/is associated with inflammatory events and/or
proliferative and hypertrophic tissue and vessel transformation. This can
be in particular disorders and/or injuries of the lung or the
cardiovascular system, or it may be sepsis, cancerous disorders or other
inflammatory disorders.

[0005] It is generally assumed that elastase-mediated pathological
processes are based on a displaced equilibrium between free elastase and
endogenous elastase inhibitor protein (mainly alpha-1 antitrypsin, AAT)
[Neutrophils and protease/antiprotease imbalance, Stockley, Am. J.
Respir. Crit. Care Med. 160, 49-52 (1999)]. AAT is present in large
excess in the plasma and thus very rapidly neutralizes free HNE. The
concentration of free elastase is elevated in various pathological
processes, so that there is a local shift in the balance between protease
and protease inhibitor in favor of the protease. In addition,
membrane-associated elastase of the activated PMN cells is very
substantially protected from inhibition by AAT. The same applies to free
elastase, which is located in a microcompartment which is difficult to
access between the neutrophilic cell and the adjoining tissue cell (for
example endothelial cell). In addition, strong oxidizing conditions
prevail in the vicinity of activated leukocytes (oxidative burst), and
thus AAT is oxidized and loses several orders of magnitude in the
inhibitory effect.

[0006] Novel elastase-inhibiting active compounds (exogenously
administered inhibitors of HNE) ought accordingly to have a low molecular
weight in order to be able also to reach and inhibit the
membrane-associated HNE and the HNE present in the protected
microcompartment (see above). Also necessary for this purpose is good in
vivo stability of the substances (low in vivo clearance). In addition,
these compounds ought to be stable under oxidative conditions in order
not to lose inhibitory power in the pathological process.

[0007] Pulmonary arterial hypertension (PAH) is a progressive lung
disorder which, untreated, leads to death on average within 2.8 years
after being diagnosed. An increasing constriction of the pulmonary
circulation leads to increased stress on the right heart, which may
develop into right heart failure. By definition, the mean pulmonary
aterial pressure (mPAP) in case of chronic pulmonary hypertension is
>25 mmHg at rest or >30 mmHg during exertion (normal value <20
mmHg). The pathophysiology of pulmonary arterial hypertension is
characterized by vasoconstriction and remodeling of the pulmonary
vessels. In chronic PAH there is neomuscularization of initially
unmuscularized pulmonary vessels, and the vascular muscles of the already
muscularized vessels increase in circumference. This increasing
obliteration of the pulmonary circulation results in progressive stress
on the right heart, which leads to a reduced output from the right heart
and eventually ends in right heart failure (M. Humbert et al., J. Am.
Coll. Cardiol. 2004, 43, 13S-24S). PAH is an extremely rare disorder,
with a prevalence of 1-2 per million. The average age of the patients has
been estimated to be 36 years, and only 10% of the patients were over 60
years of age. Distinctly more women than men are affected (G. E. D'Alonzo
et al., Ann. Intern. Med. 1991, 115, 343-349).

[0008] Despite all the advances in the therapy of pulmonary arterial
hypertension there is as yet no prospect of cure of this serious
disorder. Standard therapies available on the market (for example
prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase
inhibitors) are able to improve the quality of life, the exercise
tolerance and the prognosis of the patients. The principles of these
therapies are primarily hemodynamic, influencing vessel tone but having
no direct influence on the pathogenic remodeling processes. In addition,
the possibility of using these medicaments is restricted through the
sometimes serious side effects and/or complicated types of
administration. The period over which the clinical situation of the
patients can be improved or stabilized by specific monotherapy is limited
(for example owing to the development of tolerance). Eventually the
therapy escalates and thus a combination therapy is applied, where a
plurality of medicaments must be given concurrently.

[0009] Novel combination therapies are one of the most promising future
therapeutic options for the treatment of pulmonary arterial hypertension.
In this connection, the finding of novel pharmacological mechanisms for
the treatment of PAH is of particular interest (Ghofrani et al., Herz
2005, 30, 296-302; E. B. Rosenzweig, Expert Opin. Emerging Drugs 2006,
11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733).
Therapeutic options which intervene directly in the remodeling event
(antiremodeling mechanisms reverse remodeling mechanisms) in particular
might form the basis for a more causal treatment and thus be of great
advantage for the patients. In this connection, it will be possible to
combine known and novel therapies. In order to minimize the risk of
interfering medicament-medicament interactions in such a combination
therapy, these novel active compounds ought inhibit metabolizing P450 CYP
enzymes only to a very small extent or not at all.

[0010] These days, one proceeds on the assumption that elastase plays a
central role in pathological remodeling. It has been possible to find a
fragmentation of connective tissue (internal elastic lamina) in animal
models and in patients with elevated pulmonary arterial blood pressure
(pulmonary arterial hypertension) [Rabinovitch et al., Lab. Invest. 55,
632-653 (1986)], and it was possible to show in animal models of
pulmonary arterial hypertension (hypoxic rat and mouse model,
monocrotaline rat model) that elastase activity was increased and was
associated with the fragmentation of connective tissue [Todorovich-Hunter
et al., Am. Rev. Respir. Dis. 146, 213-223 (1992)]. It is suspected that
the tissue remodeling to be observed during the disease process of
pulmonary arterial hypertension is induced by an elastase-mediated
release of connective tissue-associated growth factors, for example of
basic fibroblast growth factor (bFGF) [Rabinovitch, Am. J. Physiol. 277,
L5-L12 (1999)]. It was possible to show a positive effect with an
overexpressed elastase inhibitor protein in the hypoxic mouse model of
pulmonary arterial hypertension [Zaidi et al., Circulation 105, 516-521
(2002)]. It was possible to show a positive effect with synthetic
low-molecular-weight elastase inhibitors in the monocrotaline rat model
of pulmonary arterial hypertension; in this case a beneficial effect on
tissue remodeling was also to be noted [Cowan et al., Nature Med. 6,
698-702 (2000)]. However, all previously disclosed low-molecular-weight
elastase inhibitors have low selectivity, are chemically reactive and/or
have only limited oral availability, thus to date thwarting clinical
development of an oral elastase inhibitor for these indications.

[0013] Other types of pulmonary hypertension include, for example, the
pulmonary hypertension associated with left heart disorders, for example
with ventricular or valvular disorders, the pulmonary hypertension
associated with disorders of the respiratory tract and/or of the lungs,
for example with chronic obstructive lung disease, interstitial lung
disease or pulmonary fibrosis, the pulmonary hypertension attributable to
chronic thrombotic and/or embolic disorders, for example associated with
thromboembolic obstruction of pulmonary arteries, and the pulmonary
hypertension caused by generally inflammatory disease processes or by
special causes (for example associated with schistosomiasis, sarcoidosis
and neoplastic diseases).

[0014] Chronic obstructive pulmonary disease (COPD) is a pulmonary disease
which progresses slowly and is characterized by obstruction of breathing
caused by pulmonary emphysema and/or chronic bronchitis. First symptoms
of the disorder generally appear from the fourth to the fifth decade of
life onwards. In the years that follow, the short breath frequently
worsens and a cough, associated with extensive and sometimes prolonged
discharge and obstructed breathing up to breathlessness (dyspnea),
manifests itself. COPD is primarily a smoker's disease: smoking is
responsible for 90% of all cases of COPD and 80-90% of all deaths caused
by COPD. COPD is a major medical problem and represents the sixth most
frequent cause of death world-wide. About 4-6% of people over the age of
45 are affected.

[0015] Although the obstruction of breathing may only be partial and
temporal, COPD cannot be cured. Accordingly, the target of the treatment
is to improve the quality of life, to ameliorate the symptoms, to prevent
acute worsening and to slow the progressive impairment of pulmonary
function. Existing pharmacotherapies, which have hardly changed over the
last two to three decades, are the use of bronchodilators to open up
blocked respiratory paths, and in certain situations corticosteroids to
control the inflammation of the lung [P. J. Barnes, N. Engl. J. Med. 343,
269-280 (2000)]. The chronic inflammation of the lung, caused by
cigarette smoke or other irritants, is the force behind the development
of the disease. The mechanism on which it is based involves immune cells
which, during the course of the inflammatory reaction of the lung,
secrete various chemokines. This attracts neutrophilic cells and
subsequently alveolar macrophages to the connective tissue of the lung
and the lumen. Neutrophilic cells secrete a protease cocktail which
contains mainly HNE and protease 3. This causes the local
protease/antiprotease balance to shift in favor of the proteases,
resulting inter alia in an unchecked elastase activity and as a
consequence thereof an excess degradation of the elastin of the alveolar
cells [J. E. Gadek et al., J. Clin. Invest. 68, 889-898 (1981); Z. Werb
et al., J. Invest. Dermatol. 79, 154-159 (1982); A. Janoff, Am. Rev.
Respir. Dis. 132, 417-433 (1985); P. J. Barnes, N. Engl. J. Med. 343,
269-280 (2000)]. This tissue degradation causes the bronchii to collapse.
This is associated with a reduced elasticity of the lung, which leads to
obstructed breathing and impaired respiration. In addition, frequent and
persistent inflammation of the lung may lead to remodeling of the
bronchii and as a consequence to the formation of lesions. Such lesions
contribute to the chronic cough which characterizes chronic bronchitis.

[0016] Alpha-1 antitrypsin (AAT) is a small endogenous protein and
represents, as mentioned above, the most important endogenous elastase
inhibitor. In patients having a genetic deficiency of this protein
(AADT), the protease/antiprotease balance is shifted. Accordingly, in
AADT patients, the effective radius and the duration of action of HNE is
increased by a factor of 2.5 and 6.5, respectively [T. G. Liou and E. J.
Campbell, Biochemistry 1995, 16171-16177]. AADT patients have an
increased risk of developing pulmonary emphysema or COPD, and in many
AADT patients a lung transplant is indicated.

[0017] Bronchiectasis is understood as an abnormal dilation of the
bronchial tree. Two forms may be distinguished: sack-shaped localized
bronchiectases and generalized, cylindrical bronchiectases.
Bronchiectases may be congenital; however, in most cases they are
acquired and are found in particular in smokers. Owing to the dilation,
drainage of the bronchial secretions is rendered more difficult, and the
retained bronchial secretions promote infections. Frequently,
bronchiectases are also encountered in the case of congenital disorders
of the mucosa such as mucoviscidosis with abnormal viscosity of the
bronchial secretions and in the case of ciliary dyskinesia syndrome. In
the case of this syndrome (Kartagener syndrome), the architecture and
function of the cilia and thus drainage of the secretions are impaired.
Other causes of bronchiectases may be obstructions proximal to the
ectasis, for example by tumors or foreign bodies. Recurrent and
persisting infections weakening the bronchial walls are also thought to
be causal. Furthermore, there are bronchiectasias which can not be
connected unambiguously to states of infection or exogenic noxa
(idiopathic bronchiectasias).

[0018] Bronchiectasia is characterized by migration of neutrophils into
the pulmonary tissue. The patients show a marked imbalance between
neutrophilic activity and protective inhibitor proteins, resulting in
damage to the pulmonary tissue by the proteases (mainly HNE) secreted by
the neutrophils [Schaaf et al., Respiration 67, 52-59 (2000)].

[0019] Bronchiolitis obliterans is an inflammation of the bronchioli with
destruction of the epithelium and formation of a fibrin-rich exudate in
the bronchioli and the neighbouring alveoli. Organization of the exudate
results in plugs of connective tissue reaching from the bronchioli into
the alveoli. The disease is characterized by an increased number of
neutrophils in the respiratory tract and an imbalance between free
elastase and the endogenous elastase inhibitor protein [Elssner et al.,
Transpl. Infect. Dis. 3, 168-176 (2001)] Prior infections and medicaments
are being discussed as possible causes. The disease may also occur in the
context of a transplant rejection.

[0020] Acute lung injury (ALI) and the more pronounced form thereof, acute
respiratory distress syndrome (ARDS), are serious disorders associated
with a mortality of 50-60%. According to the definition of the North
American-European Consensus Conference (NAECC) of 1994, ALI and ARDS are
defined by an acute onset, bilateral radiologically visible infiltrates,
a PaO2/FiO2 index of ≦300 mmHg (ALI) or ≦200 mmHg
(ARDS), a pulmonary capillary wedge pressure of <18 mmHg and no
clinical evidence of left atrial hypertension.

[0021] The development of acute lung injury may be preceded both by
pulmonary and extrapulmonary disorders. Aspiration of stomach content,
pneumonias, smoke poisoning, pulmonary contusion and near-drowning are
considered to be lung-specific predisposing factors. In particular the
aspiration of stomach content and pneumonias are frequently seen as
initial disorders of ALI/ARDS of pulmonary origin. The most frequent
indirect events are polytrauma, sepsis, repeated blood transfusions,
acute pancreatitis and burns. The incidence is 17.9 cases of ALI and 13.5
cases of ARDS per 100 000 inhabitants and year [Luhr et al., Am. J.
Respir. Crit. Care Med. 159, 1849-1861 (1999)].

[0022] A central role in the development of these disorders is played by
the massive inflammatory changes in the lung, which are triggered by a
widely branched system of mediators. An important role in the development
of lung injury is also played by neutrophilic granulocytes, the number of
which increases permanently during the inflammatory process
[Chollet-Martin et al., Am. J. Respir. Crit. Care Med. 154, 594-601
(1996)]. The action of the mediators causes damage to the
alveolocapillary membranes, and this results in an increased permeability
of the alveolar capillary barrier. Owing to the increased permeability,
protein-rich fluid can permeate into the alveolae and also into the
interstitial space; a low-pressure pulmonary edema develops.
Characteristic for ALI/ARDS, this is a noncardiogenic edema. The edema
fluid contains mainly fibrin, erythrocytes, leukocytes, hyaline membranes
and other proteins. Together with the products of activated neutrophils,
the protein-rich exudate leads to dysfunction of the surfactant. The
inflammatory processes cause damage and loss of pneumocytes of type II,
which form surfactant, resulting in a reduced surfactant production. The
surfactant deficit increases the surface tension in the alveolae; the
alveolae collapse and atelectases are formed. With perfusion being
maintained, there is thus a ventilation/perfusion imbalance resulting in
an increase of the pulmonary right-left shunt. Furthermore, compliance is
reduced, and in contrast the alveolar dead space is increased because
there are areas which are ventilated but, owing to pulmonary
hypertension, no longer sufficiently perfused.

[0023] An increased elastase activity, which correlates to the severity of
the lung injury, could be measured in the bronchoalveolar lavage fluid
(BALF) of ARDS patients. In animal models where the lung is injured (for
example by administration of LPS), this effect can be reproduced. Here,
treatment with elastase inhibitors (for example sivelestat or elafin,
vide infra,) reduces the elastase activity in the BALF considerably and
improves lung function.

[0024] In Japan and South Korea, an elastase inhibitor (sivelestat,
Elaspol®) is approved for the treatment of acute lung injury
associated with SIRS. The reversible, but reactive compound has only a
relatively weak effect on HNE (Ki 200 nM) and also acts on the
pancreas elastase (IC50 5.6 μM). The active compound is
administered intravenously, oral administration is not possible.

[0025] Elafin and structural analogs are also investigated as
therapeutically useful elastase inhibitors. Elafin is an endogenous small
protein which inhibits both elastase and proteinase 3. However, owing to
the proteinergic character, oral administration of elafin is not
possible.

[0026] It is an object of the present invention to provide novel
substances acting as low-molecular-weight, non-reactive and selective
inhibitors of human neutrophil elastase (HNE), which are suitable as such
for the treatment and/or prevention in particular of pulmonary disorders
and disorders of the cardiovascular system.

[0027] WO 2004/024700, WO 2004/024701, WO 2005/082863 and WO 2005/082864
disclose various 1,4-diaryldihydropyrimidin-2-one derivatives as HNE
inhibitors for the treatment of chronic obstructive pulmonary disease,
acute coronary syndrome, myocardial infarction and heart failure. Di- and
multimers of such compounds for the treatment of respiratory disorders
are claimed in WO 2006/082412, WO 2006/136857 and WO 2007/042815. WO
2008/003412 discloses the use of certain 1,4-diaryldihydropyrimidin-2-one
derivatives for treating pulmonary arterial hypertension.
4-Aryldihydropyrimidin-2-one derivatives as inhibitors of the calcium
channel function for the treatment of hypertension are described in WO
2005/009392.

[0028] It has now been found that certain 1,4-diaryldihydropyrimidin-2-one
derivatives are particularly suitable for the treatment and/or prevention
of disorders. These compounds described below are low-molecular-weight,
non-reactive and selective inhibitors of human neutrophil elastase (HNE)
which, surprisingly, effect a considerably stronger inhibition of this
protease than the compounds known from the prior art. In addition, the
compounds according to the invention have an unexpectedly low in vitro
clearance with respect to hepatocytes and thus have improved metabolic
stability. Moreover, some of the compounds according to the invention
have good solubility in aqueous systems which is advantageous with regard
to their formulatibility and/or intravenous administrability.
Accordingly, the substances of the present invention are promising
starting points for novel medicaments for the treatment and/or prevention
of in particular disorders of the lung and the cardiovascular system.

[0029] Specifically, the present invention relates to compounds of the
general formula (I)

##STR00001##

in which [0030] Z represents a sulfonamide grouping of the formula

##STR00002##

[0030] or represents a sulfoximine grouping of the formula

##STR00003##

in which [0031] * denotes the point of attachment to the phenyl ring,
[0032] RZ1 represents hydrogen, or represents
(C1-C6)-alkyl which may be substituted by hydroxyl,
(C1-C4)-alkoxy, amino, mono- or di-(C1-C4)-alkylamino
and up to three times by fluorine, [0033] RZ2 represents hydrogen,
(C3-C6)-cycloalkyl, 4- to 6-membered heterocyclyl or 5- or
6-membered heteroaryl [0034] or [0035] represents
(C1-C6)-alkyl which may be substituted by hydroxyl,
(C1-C4)-alkoxy, amino, mono- or
di-(C1-C4)-alkylamino, (C1-C4)-alkylcarbonylamino,
(C1-C4)-alkoxycarbonylamino, (C1-C4)-alkylsulfinyl,
(C1-C4)-alkylsulfonyl, (C3-C6)-cycloalkyl, phenyl, 4-
to 6-membered heterocyclyl, 5- or 6-membered heteroaryl or a group of the
formula --C(═O)--NRZ5RZ6 and up to three times by fluorine,
[0036] where the alkoxy substituent mentioned for its part may be
substituted up to three times by fluorine, [0037] and where [0038] the
heterocyclyl groups mentioned may be substituted up to two times by
identical or different substituents from the group consisting of
fluorine, (C1-C4)-alkyl, oxo, hydroxyl,
(C1-C4)-alkoxy, amino, mono- and
di-(C1-C4)-alkylamino [0039] and [0040] the phenyl group
mentioned and the heteroaryl groups mentioned may be substituted up to
two times by identical or different substituents from the group
consisting of fluorine, chlorine, cyano, (C1-C4)-alkyl,
difluoromethyl, tri-fluoromethyl and (C1-C4)-alkoxy, [0041] and
where [0042] RZ5 and RZ6 are identical or different and
independently of one another represent hydrogen or
(C1-C4)-alkyl [0043] or [0044] RZ5 and RZ6 together
with the nitrogen atom to which they are attached form a 4- to 6-membered
aza heterocycle which may contain a further ring heteroatom from the
group consisting of N, O and S and may be substituted by
(C1-C4)-alkyl, oxo, hydroxyl, (C1-C4)-alkoxy, amino,
mono- or di-(C1-C4)-alkylamino, [0045] or [0046] RZ1 and
RZ2 together with the nitrogen atom to which they are attached form
a 4- to 10-membered aza heterocycle which may contain a further ring
heteroatom from the group consisting of N, O and S and may be substituted
up to two times by identical or different substituents from the group
consisting of fluorine, (C1-C4)-alkyl, oxo, hydroxyl,
(C1-C4)-alkoxy, amino, mono- and
di-(C1-C4)-alkylamino, [0047] RZ3 represents
(C1-C6)-alkyl which may be substituted by
(C3-C6)-cycloalkyl or up to three times by fluorine, or
represents phenyl which may be substituted up to two times by identical
or different substituents from the group consisting of fluorine,
chlorine, cyano, (C1-C4)-alkyl, difluoromethyl and
trifluoromethyl, or represents (C3-C6)-cycloalkyl, [0048] and
[0049] RZ4 represents hydrogen, (C1-C4)-alkyl or
(C3-C6)-cycloalkyl, [0050] R1 represents cyano or
acetyl, [0051] R2 represents hydrogen, represents
(C1-C4)-alkyl or (C1-C4)-alkylsulfonyl which may be
substituted up to three times by fluorine, or represents a group of the
formula --CH2--C(═O)--NH--R4 in which [0052] R4
represents hydrogen, represents (C1-C4)-alkyl which may be
substituted by (C3-C6)-cycloalkyl or up to three times by
fluorine, or represents (C3-C6)-cycloalkyl, [0053] and [0054]
R5 represents hydrogen, fluorine or chlorine, [0055] and their
salts, solvates and solvates of the salts.

[0056] Compounds according to the invention are the compounds of the
formula (I) and the salts, solvates and solvates of the salts thereof,
the compounds of the formulae mentioned hereinafter and encompassed by
formula (I) and the salts, solvates and solvates of the salts thereof,
and the compounds which are mentioned hereinafter as exemplary
embodiments and encompassed by formula (I) and the salts, solvates and
solvates of the salts thereof, insofar as the compounds encompassed by
formula (I) and mentioned hereinafter are not already salts, solvates and
solvates of the salts.

[0057] The compounds according to the invention may, depending on their
structure, exist in various stereoisomeric forms, i.e. in the form of
configurational isomers or, if appropriate, also in the form of
conformational isomers (enantiomers and/or diastereomers, including those
in the case of atropisomers). The present invention therefore embraces
the enantiomers and diastereomers and also their respective mixtures. The
stereoisomerically pure constituents can be isolated in a known manner
from such mixtures of enantiomers and/or diastereomers.

[0058] If the compounds according to the invention may occur in tautomeric
forms, the present invention encompasses all tautomeric forms.

[0059] Salts which are preferred for the purposes of the present invention
are physiologically acceptable salts of the compounds according to the
invention. Also encompassed are salts which are themselves unsuitable for
pharmaceutical uses but can be used for example for isolating or
purifying the compounds according to the invention.

[0061] Physiologically acceptable salts of the compounds according to the
invention also include salts of conventional bases such as, by way of
example and preferably, alkali metal salts (for example sodium salts and
potassium salts), alkaline earth metal salts (for example calcium salts
and magnesium salts) and ammonium salts derived from ammonia or organic
amines having 1 to 16 carbon atoms, such as, by way of example and
preferably, ethylamine, diethylamine, triethylamine,
ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine,
N-methylmorpholine, arginine, lysine, ethylenediamine and
N-methylpiperidine.

[0062] Solvates refers for the purposes of the invention to those forms of
the compounds according to the invention which form, in the solid or
liquid state, a complex by coordination with solvent molecules. Hydrates
are a specific form of solvates in which the coordination takes place
with water. Hydrates are preferred solvates in the context of the present
invention.

[0063] The present invention additionally encompasses prodrugs of the
compounds of the invention. The term "prodrugs" encompasses compounds
which themselves may be biologically active or inactive, but are
converted during their residence time in the body into compounds
according to the invention (for example by metabolism or hydrolysis).

[0064] In the context of the present invention, the substituents have the
following meaning, unless specified otherwise:

[0065] (C1-C6)-Alkyl and (C1-C4)-alkyl stand for the
purposes of the invention for a straight-chain or branched alkyl radical
having respectively 1 to 6 and 1 to 4 carbon atoms. A straight-chain or
branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples
which may be preferably mentioned are: methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl,
n-pentyl, neopentyl and n-hexyl.

[0066] (C1-C4)-Alkylcarbonyl stands for the purposes of the
invention for a straight-chain or branched alkyl radical which has 1 to 4
carbon atoms and is attached via a carbonyl group. Examples which may be
preferably mentioned are: acetyl, propionyl, n-butyryl, isobutyryl,
n-pentanoyl and pivaloyl.

[0067] (C1-C4)-Alkoxy stands for the purposes of the invention
for a straight-chain or branched alkoxy radical having 1 to 4 carbon
atoms. Examples which may be preferably mentioned are: methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

[0068] (C1-C4)-Alkoxycarbonyl stands for the purposes of the
invention for a straight-chain or branched alkoxy radical having 1 to 4
carbon atoms which is attached via a carbonyl group. Examples which may
be preferably mentioned are: methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and
tert-butoxycarbonyl.

[0069] Mono-(C1-C4)-alkylamino stands for the purposes of the
invention for an amino group having a straight-chain or branched alkyl
substituent having 1 to 4 carbon atoms. Examples which may be preferably
mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino,
n-butylamino and tert-butylamino.

[0070] Di-(C1-C4)-alkylamino stands for the purposes of the
invention for an amino group having two identical or different
straight-chain or branched alkyl substituents having in each case 1 to 4
carbon atoms. Examples which may be preferably mentioned are:
N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,
N-methyl-N-n-propylamino, N-isopropyl-N-methylamino,
N-isopropyl-N-n-propylamino, N,N-diisopropylamino,
N-n-butyl-N-methylamino and N-tert-butyl-N-methylamino.

[0071] (C1-C4)-Alkylcarbonylamino stands for the purposes of the
invention for an amino group having a straight-chain or branched
alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl
radical and is attached via the carbonyl group to the nitrogen atom.
Examples which may be preferably mentioned are: acetylamino,
propionylamino, n-butyrylamino, isobutyrylamino, n-pentanoylamino and
pivaloylamino.

[0072] (C1-C4)-Alkoxycarbonylamino stands for the purposes of
the invention for an amino group having a straight-chain or branched
alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkoxy
radical and is attached via the carbonyl group to the nitrogen atom.
Examples which may be preferably mentioned are: methoxycarbonylamino,
ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino,
n-butoxycarbonylamino and tert-butoxycarbonylamino.

[0073] (C1-C4)-Alkylsulfinyl stands for the purposes of the
invention for a straight-chain or branched alkyl radical which has 1 to 4
carbon atoms and is attached via a sulfinyl group [--S(═O)--].
Examples which may be preferably mentioned are: methylsulfinyl,
ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl and
tert-butylsulfinyl.

[0074] (C1-C4)-Alkylsulfonyl stands for the purposes of the
invention for a straight-chain or branched alkyl radical which has 1 to 4
carbon atoms and is attached via a sulfonyl group [--S(═O)2--].
Examples which may be preferably mentioned are: methylsulfonyl,
ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and
tert-butylsulfonyl.

[0075] (C3-C6)-Cycloalkyl stands for the purposes of the
invention for a monocyclic saturated cycloalkyl group having 3 to 6 ring
carbon atoms. Examples which may be preferably mentioned are:
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0076] A 4- to 10-membered aza heterocycle stands for the purposes of the
invention for a mono- or optionally bicyclic saturated heterocycle which
has a total of 4 to 10 ring atoms, which contains a ring nitrogen atom
through which it is also attached, and which may additionally contain a
further ring heteroatom from the group consisting of N, O and S. Examples
which may be preferably mentioned are: azetidinyl, pyrrolidinyl,
pyrazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl,
hexahydro-1,4-diazepinyl, octahydroazocinyl,
octahydropyrrolo[3,4-b]pyrrolyl, octahydroindolyl, octahydroisoindolyl,
octahydropyrrolo[3,2-b]pyridyl, octahydropyrrolo[3,4-b]pyridyl,
octahydropyrrolo[3,4-c]pyridyl, octahydropyrrolo[1,2-a]pyrazinyl,
decahydroquinolinyl, decahydroisoquinolinyl,
octahydropyrido[1,2-a]pyrazinyl, 7-azabicyclo [2.2.1]heptyl,
3-azabicyclo[3.2.0]heptyl, 3-azabicyclo [3.2.1]octyl, 8-azabicyclo
[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl and 9-azabicyclo
[3.3.1]nonyl. Preference is given to a mono- or optionally bicyclic 5- to
10-membered aza heterocycle which may, in addition to the nitrogen atom,
contain a further ring heteroatom from the group consisting of N and O,
such as, for example, pyrrolidinyl, pyrazolidinyl, 1,3-oxazolidinyl,
piperidinyl, piperazinyl, morpholinyl, hexahydroazepinyl,
hexahydro-1,4-diazepinyl, octahydroazocinyl,
octahydropyrrolo[3,4-b]-pyrrolyl, octahydroindolyl, octahydroisoindolyl,
octahydropyrrolo[3,2-b]pyridyl, octahydropyrrolo[3,4-b]pyridyl,
octahydropyrrolo[3,4-c]pyridyl, octahydropyrrolo[1,2-a]pyrazinyl,
decahydroquinolinyl, decahydroisoquinolinyl,
octahydropyrido[1,2-a]pyrazinyl, 7-azabicyclo[2.2.1]heptyl,
3-azabicyclo[3.2.0]heptyl, 3-Aazabicyclo[3.2.1]octyl,
8-azabicyclo[3.2.1]-octyl, 8-oxa-3-azabicyclo[3.2.1]octyl and
9-azabicyclo[3.3.1]nonyl. Particular preference is given to a monocyclic
5- or 6-membered aza heterocycle which may, in addition to the nitrogen
atom, contain a further ring heteroatom from the group consisting of N
and O, such as, for example, pyrrolidinyl, 1,3-oxazolidinyl, piperidinyl,
piperazinyl and morpholinyl.

[0077] 4- to 6-membered heterocyclyl stands for the purposes of the
invention for a monocyclic saturated heterocycle which has a total of 4
to 6 ring atoms, which contains one or two ring heteroatoms from the
group consisting of N, O and S and which is attached via a ring carbon
atom or optionally a ring nitrogen atom. Examples which may be mentioned
are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl,
tetrahydrofuranyl, 1,3-oxazolidinyl, thiolanyl, 1,3-thiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl,
tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl. Preference is
given to a 4- to 6-membered heterocycle having one or two ring
heteroatoms from the group consisting of N and O, such as, for example,
azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,
piperazinyl, tetrahydropyranyl, 1,4-dioxanyl and morpholinyl. Particular
preference is given to a 5- or 6-membered heterocycle having one or two
ring heteroatoms from the group consisting of N and O, such as, for
example, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,
tetrahydropyranyl, 1,4-dioxanyl and morpholinyl.

[0078] 5- or 6-membered heteroaryl stands for the purposes of the
invention for an aromatic heterocycle (heteroaromatic) having a total of
5 or 6 ring atoms which contains up to three identical or different ring
heteroatoms from the group consisting of N, O and S and which is attached
via a ring carbon atom or, if appropriate, via a ring nitrogen atom.
Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl,
imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl
and triazinyl. Preference is given to 5- or 6-membered heteroaryl
radicals having one or two ring heteroatoms from the group consisting of
N, O and S, such as, for example, furyl, pyrrolyl, thienyl, pyrazolyl,
imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl,
pyrimidinyl, pyridazinyl and pyrazinyl.

[0079] For the purposes of the invention, an oxo substituent is an oxygen
atom which is attached via a double bond to a carbon atom.

[0080] When radicals in the compounds according to the invention are
substituted, the radicals may be mono- or polysubstituted, unless
specified otherwise. For the purposes of the present invention, the
meanings of all radicals which occur more than once are independent of
one another. Preference is given to substitution by one or two identical
or different substituents. Very particularly preferred is substitution by
one substituent.

[0081] Preferred for the purposes of the present invention are compounds
of the formula (I) in which [0082] Z represents a sulfonamide grouping of
the formula

##STR00004##

[0082] or represents a sulfoximine grouping of the formula

##STR00005##

in which [0083] * denotes the point of attachment to the phenyl ring,
[0084] RZ1 represents hydrogen or represents (C1-C4)-alkyl
which may be substituted by hydroxyl, methoxy or ethoxy, [0085] RZ2
represents hydrogen, (C3-C6)-cycloalkyl, 5- or 6-membered
heterocyclyl or 5- or 6-membered heteroaryl [0086] or [0087] represents
(C1-C4)-alkyl which may be substituted by hydroxyl,
(C1-C4)-alkoxy, amino, mono- or
di-(C1-C4)-alkylamino, (C1-C4)-alkylcarbonylamino,
(C1-C4)-alkoxycarbonylamino, (C1-C4)-alkylsulfinyl,
(C1-C4)-alkylsulfonyl, (C3-C6)-cycloalkyl, phenyl, 5-
or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or a group of the
formula --C(═O)--NRZ5RZ6 and up to three times by fluorine,
[0088] where the alkoxy substituent mentioned for its part may be
substituted up to three times by fluorine, [0089] and where [0090] the
heterocyclyl groups mentioned may be substituted up to two times by
identical or different substituents from the group consisting of
(C1-C4)-alkyl, oxo, hydroxyl and (C1-C4)-alkoxy
[0091] and [0092] the phenyl group mentioned and the heteroaryl groups
mentioned may be substituted up to two times by identical or different
substituents from the group consisting of fluorine, chlorine, cyano,
(C1-C4)-alkyl, trifluoromethyl and (C1-C4)-alkoxy,
[0093] and where [0094] RZ5 and RZ6 are identical or different
and independently of one another represent hydrogen or
(C1-C4)-alkyl [0095] or [0096] RZ5 and RZ6 together
with the nitrogen atom to which they are attached form a 5- or 6-membered
aza heterocycle which may contain a further ring heteroatom from the
group consisting of N and O and may be substituted by
(C1-C4)-alkyl, oxo, hydroxyl or (C1-C4)-alkoxy,
[0097] or [0098] RZ1 and RZ2 together with the nitrogen atom to
which they are attached form a 5- to 10-membered aza heterocycle which
may contain a further ring heteroatom from the group consisting of N and
O and may be substituted up to two times by identical or different
substituents from the group consisting of (C1-C4)-alkyl, oxo,
hydroxyl and (C1-C4)-alkoxy, [0099] RZ3 represents
(C1-C4)-alkyl which may be substituted by
(C3-C6)-cycloalkyl or up to three times by fluorine, or
represents phenyl which may be substituted up to two times by identical
or different substituents from the group consisting of fluorine,
chlorine, cyano, methyl and trifluoromethyl, or represents
(C3-C6)-cycloalkyl, [0100] and [0101] RZ4 represents
hydrogen, methyl or cyclopropyl, [0102] R1 represents cyano,
[0103] R2 represents hydrogen, (C1-C4)-alkyl or
(C1-C4)-alkylsulfonyl, each of which may be substituted up to
three times by fluorine, or represents a group of the formula
--CH2--C(═O)--NH--R4 in which [0104] R4 represents
hydrogen, methyl, cyclopropyl or cyclopropylmethyl, [0105] and [0106]
R3 represents hydrogen or fluorine, [0107] and their salts, solvates
and solvates of the salts.

[0108] Particular preference in the context of the present invention is
given to compounds of the formula (I) in which [0109] Z represents a
sulfonamide grouping of the formula

##STR00006##

[0109] in which [0110] * denotes the point of attachment to the phenyl
ring, [0111] RZ1 represents hydrogen, methyl or 2-hydroxyethyl,
[0112] RZ2 represents hydrogen, cyclopropyl, 5- or 6-membered
heterocyclyl or 5- or 6-membered heteroaryl [0113] or [0114] represents
(C1-C4)-alkyl which may be substituted by hydroxyl, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino,
acetylamino, cyclopropyl, 5- or 6-membered heterocyclyl or a group of the
formula --C(═O)--NRZ5RZ6, [0115] where methoxy and ethoxy
substituents mentioned for their part may be substituted up to three
times by fluorine, [0116] and where [0117] the heterocyclyl groups
mentioned may be substituted up to two times by identical or different
substituents from the group consisting of methyl, ethyl, oxo, hydroxyl,
methoxy and ethoxy [0118] and [0119] the heteroaryl group mentioned may
be substituted up to two times by identical or different substituents
from the group consisting of fluorine, chlorine, cyano, methyl, ethyl,
trifluoromethyl, methoxy and ethoxy, [0120] and where [0121] RZ5 and
RZ6 independently of one another represent hydrogen or methyl or
together with the nitrogen atom to which they are attached form a
pyrrolidine, piperidine or morpholine ring, [0122] or [0123] RZ1
and RZ2 together with the nitrogen atom to which they are attached
form a pyrrolidine, piperidine or morpholine ring, [0124] R1
represents cyano, [0125] R2 represents hydrogen, methyl,
methylsulfonyl or the group of the formula
--CH2--C(═O)--NH2, [0126] and [0127] R3 represents
hydrogen, [0128] and their salts, solvates and solvates of the salts.

[0129] Particular preference in the context of the present invention is
also given to compounds of the formula (I) in which [0130] Z represents a
sulfoximine grouping of the formula

##STR00007##

[0130] in which [0131] * denotes the point of attachment to the phenyl
ring [0132] and [0133] RZ3 represents (C1-C4)-alkyl which
may be substituted by cyclopropyl or up to three times by fluorine, or
represents cyclopropyl, [0134] R1 represents cyano, [0135] R2
represents hydrogen, methyl, methylsulfonyl or the group of the formula
--CH2--C(═O)--NH2, [0136] and [0137] R3 represents
hydrogen, [0138] and their salts, solvates and solvates of the salts.

[0139] Very particular preference in the context of the present invention
is given to compounds of the formula (I) in which [0140] Z represents a
sulfonamide grouping of the formula

[0140] ##STR00008## [0141] in which [0142] * denotes the point of
attachment to the phenyl ring [0143] and [0144] RZ2 represents
hydrogen, methyl or the group of the formula
--CH2--C(═O)--NH2, [0145] R1 represents cyano,
[0146] R2 represents hydrogen, methyl or methylsulfonyl, [0147] and
[0148] R3 represents hydrogen, [0149] and their salts, solvates and
solvates of the salts.

[0150] Very particular preference in the context of the present invention
is also given to compounds of the formula (I) in which [0151] Z
represents a sulfoximine grouping of the formula

##STR00009##

[0151] in which [0152] * denotes the point of attachment to the phenyl
ring, [0153] R1 represents cyano, [0154] R2 represents
hydrogen, methyl or methylsulfonyl, [0155] and [0156] R3 represents
hydrogen, [0157] and their salts, solvates and solvates of the salts.

[0158] Of particular importance are compounds of the formula (I) having
the S configuration, shown in formula (Lent), at the 4-position of the
dihydropyrimidinone ring

##STR00010## [0159] where Z, R1, R2 and R3 each have the
meanings given above, [0160] and their salts, solvates and solvates of
the salts.

[0161] Specific radical definitions given in the respective combinations
or preferred combinations of radicals are, independently of the
combinations of radicals given in each case, also replaced by any radical
definitions of other combinations.

[0162] Very particular preference is given to combinations of two or more
of the preferred ranges mentioned above.

[0163] The invention furthermore provides a process for preparing the
compounds of the formula (I) according to the invention in which [0164] Z
represents a sulfonamide grouping of the formula

##STR00011##

[0164] in which [0165] * denotes the point of attachment to the phenyl
ring [0166] and [0167] RZ1 and RZ2 have the meanings given
above, [0168] characterized in that initially an aniline derivative of
the formula (II)

##STR00012##

[0168] in which R1, R2 and R3 have the meanings given
above, is converted with sodium nitrite and hydrochloric acid into the
corresponding diazonium salt and then reacted in a one-pot reaction with
sulfur dioxide in the presence of copper(I) chloride to give a sulfonyl
chloride of the formula (III)

##STR00013##

in which R1, R2 and R3 have the meanings given above, and
this is then reacted with an amine of the formula (IV)

##STR00014##

in which RZ1 and RZ2 have the meanings given above, if
appropriate in the presence of an auxiliary base, to give the sulfonamide
of the formula (I-A)

##STR00015##

in which R1, R2, R3, RZ1 and RZ2 have the
meanings given above, and the compounds of the formula (I-A) obtained in
this manner are, if appropriate, separated by methods known to the person
skilled in the art into their enantiomers and/or diastereomers and/or
converted with the appropriate (i) solvents and/or (ii) bases or acids
into their solvates, salts and/or solvates of the salts.

[0169] The diazotization and the subsequent sulfochlorination in process
step (II)→(III) are carried out by methods familiar to the person
skilled in the art by initially converting the aniline derivative of the
formula (II) by reaction with sodium nitrite in aqueous hydrochloric acid
at from -20° C. to 0° C. into the diazonium salt which is
then reacted further in situ at from -20° C. to +20° C.
with a saturated solution of sulfur dioxide in acetic acid in the
presence of copper(I) chloride as catalyst.

[0170] Inert solvents for the sulfonamide formation in process step
(III)+(IV)→(I-A) are customary organic solvents which do not
change under the reaction conditions. These include, for example, ethers
such as diethyl ether, diisopropyl ether, methyl tert-butyl ether,
1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons such as
pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated
hydrocarbons such as dichloromethane, 1,2-dichloroethane,
trichloromethane or chlorobenzene, or other solvents such as ethyl
acetate, acetonitrile, pyridine, dimethyl sulfoxide (DMSO),
N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or
N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such
solvents. Preference is given to using tetrahydrofuran, 1,4-dioxane,
dichloromethane or 1,2-dichloroethane.

[0171] The reaction (III)+(IV)→(I-A) is usually carried out in the
presence of an auxiliary base. Suitable for this purpose are in
particular tertiary organic amine bases such as triethylamine,
N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or
4-N,N-dimethylaminopyridine; preference is given to using triethylamine
or N,N-diisopropylethylamine. If appropriate, the reaction can also be
carried out using an excess of the amine (IV), without further addition
of an auxiliary base.

[0172] The process step (III)+(IV)→(I-A) is generally carried out
in a temperature range of from -20° C. to +60° C.,
preferably at from 0° C. to +40° C. The reaction can be
carried out at atmospheric, at elevated or at reduced pressure (for
example at from 0.5 to 5 bar); in general, the reaction is carried out at
atmospheric pressure.

[0173] The invention furthermore provides a process for preparing
compounds of the formula (I) according to the invention in which [0174] Z
represents a sulfoximine grouping of the formula

##STR00016##

[0174] in which [0175] * denotes the point of attachment to the phenyl
ring [0176] and [0177] RZ3 has the meaning given above,
characterized in that a phenyl thioether derivative of the formula (V)

##STR00017##

[0177] in which R1, R2, R3 and RZ3 have the meanings
given above, is initially oxidized with hydrogen peroxide, a peracid or a
periodate to give the sulfoxide of the formula (VI)

##STR00018##

in which R1, R2, R3 and RZ3 have the meanings given
above, then converted with 2,2,2-trifluoroacetamide and
(diacetoxyiodo)benzene in the presence of dimeric rhodium(II) acetate as
catalyst and magnesium oxide as base into an N-acylsulfoximine of the
formula (VII)

##STR00019##

in which R1, R2, R3 and RZ3 have the meanings given
above, and the trifluoroacetyl group in (VII) is then removed under basic
conditions to give the sulfoximine of the formula (I-B)

##STR00020##

[0178] in which R1, R2, R3 and RZ3 have the meanings
given above,

and the compounds of the formula (I-B) obtained in this manner are, if
appropriate, separated by methods known to the person skilled in the art
into their enantiomers and/or diastereomers and/or converted with the
appropriate (i) solvents and/or (ii) bases or acids into their solvates,
salts and/or solvates of the salts.

[0179] Suitable oxidizing agents for the process step (V)→(VI) are
in particular organic or inorganic peroxo compounds. These include, for
example, hydrogen peroxide, if appropriate with catalyst assistance,
peracids such as peracetic acid or m-chloroperbenzoic acid, or salts of
such compounds, such as sodium periodate. Preference is given to using
hydrogen peroxide, in the presence of the catalyst methyltrioxorhenium,
or sodium periodate.

[0180] The oxidation (V)→(VI) is preferably carried out in
alcoholic solvents such as methanol or ethanol, if appropriate with
addition of water, in a temperature range of from -20° C. to
+100° C., preferably at from 0° C. to +60° C.

[0181] The transformation of the sulfoxide (VI) into the
N-trifluoroacetylsulfoximine (VII) is carried out in accordance with a
method described in the literature via a metal-catalyzed oxidative
imination reaction with 2,2,2-trifluoroacetamide and
(diacetoxyiodo)benzene in the presence of dimeric rhodium(II) acetate as
catalyst and magnesium oxide as base [cf. H. Okamura and C. Bolm, Org.
Lett. 6 (8), 1305-1307 (2004)]. The reaction is preferably carried out in
the solvent dichloromethane in a temperature range of from 0° C.
to +40° C.

[0182] The removal of the trifluoroacetyl group in process step
(VII)→(I-B) is effected in a customary manner by treatment with an
alkali metal carbonate or hydroxide in an alcoholic or aqueous solvent.
Preference is given to using potassium carbonate in methanol or
acetonitrile/methanol mixtures. The reaction is generally carried out in
a temperature range of from -10° C. to +30° C.

[0183] Sulfoximine derivatives of the formula (I-C) according to the
invention

##STR00021##

in which R1, R2, R3 and RZ3 have the meanings given
above and RZ4A represents (C1-C4)-alkyl or
(C3-C6)-cycloalkyl, can be obtained by reaction of the
compounds (I-B) described above with a compound of the formula (VIII)

RZ4A--X1 (VIII),

in which RZ4A has the meaning given above and X1 represents a
leaving group such as, for example, halogen, mesylate, tosylate or
triflate, in the presence of a strong base such as, for example, sodium
tert-butoxide or potassium tert-butoxide or sodium hydride or potassium
hydride. If appropriate, the use of a phase-transfer catalyst such as
tetrabutylammonium bromide or benzyltriethylammonium chloride may be
advantageous [cf., for example, C. R. Johnson and O. M. Layergne, J. Org.
Chem. 58 (7), 1922-1923 (1993)].

[0184] The compounds of the formula (II) can be prepared analogously to
processes described in the literature, for example by condensing
4-cyano-2-nitrobenzaldehyde of the formula (IX)

##STR00022##

in the presence of an acid or an acid anhydride in a 3-component one-pot
reaction or sequentially with a keto compound of the formula (X)

##STR00023##

in which R1 has the meaning given above, and a phenylurea derivative
of the formula (XI)

##STR00024##

in which R3 has the meaning given above, to give a compound of the
formula (XII-A)

##STR00025##

in which R1 and R3 have the meanings given above, which is
then, if the radical R2 in formula (I) does not represent hydrogen,
reacted in the presence of a base with a compound of the formula (XIII)

R2A--X2 (XIII),

in which R2A has the meaning of R2 given above, but does not
represent hydrogen, and X2 represents a leaving group such as, for
example, halogen, mesylate, tosylate or triflate, to give a compound of
the formula (XII-B)

##STR00026##

in which R1, R2A and R3 have the meanings given above, and
the nitro compound of the formula (XII-A) or (XII-B) is then reduced to
the aniline derivative of the formula (II)

##STR00027##

in which R1, R2 and R3 have the meanings given above.

[0185] Suitable solvents for the process step (IX)+(X)+(XI)→(XII-A)
are customary organic solvents which do not change under the reaction
conditions. These include, for example, ethers, such as diethyl ether,
diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane,
1,4-dioxane or tetrahydrofuran, alcohols, such as methanol, ethanol,
n-propanol, isopropanol, n-butanol or tertbutanol, hydrocarbons, such as
pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated
hydrocarbons, such as dichloromethane, 1,2-dichloroethan,
trichloromethane or chlorobenzene, or other solvents, such as ethyl
acetate, acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide. It is
also possible to use mixtures of the solvents mentioned. Preference is
given to using methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane.

[0186] Suitable acids for the process step (IX)+(X)+(XI)→(XII-A)
are customary inorganic or organic acids or acid anhydrides. These
preferably include carboxylic acids, such as, for example, acetic acid or
trifluoroacetic acid, sulfonic acids, such as methanesulfonic acid,
trifluoromethanesulfonic acid or p-toluenesulfonic acid, hydrochloric
acid, sulfuric acid, phosphoric acid, phosphonic acids, or phosphoric or
phosphonic anhydrides or esters, such as polyphosphoric acid, phosphoric
acid triethyl ester, polyphosphoric acid ethyl ester, phosphorus
pentoxide or propanephosphonic anhydride. Preference is given to using
phosphoric acid triethyl ester in combination with phosphorus pentoxide.
The acid is generally employed in an amount of from 0.25 mol to 100 mol
based on 1 mol of the compound (X).

[0187] The process step (IX)+(X)+(XI)→(XII-A) is generally carried
out in a temperature range of from +20° C. to +150° C.,
preferably at from +50° C. to +100° C. The reaction can be
carried out at atmospheric, elevated or reduced pressure (for example
from 0.5 to 5 bar); in general, the process is carried out at atmospheric
pressure.

[0188] Suitable solvents for the process step
(XII-A)+(XIII)→(XII-B) are customary organic solvents which do not
change under the reaction conditions. These include, for example, ethers,
such as diethyl ether, diisopropyl ether, methyl tert-butyl ether,
1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such
as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated
hydrocarbons, such as dichloromethane, 1,2-dichloroethane,
trichloromethane or chlorobenzene, or other solvents, such as acetone,
methyl ethyl ketone, methyl tert-butyl ketone, acetonitrile, dimethyl
sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea (DMPU) or
N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such
solvents. Preference is given to using tetrahydrofuran, acetonitrile or
N,N-dimethylformamide.

[0189] Suitable bases for the process step (XII-A)+(XIII)→(XII-B)
are customary inorganic or organic bases. These include in particular
alkali metal or alkaline earth metal carbonates, such as lithium
carbonate, sodium carbonate, potassium carbonate, calcium carbonate or
caesium carbonate, alkali metal alkoxides, such as sodium tert-butoxide
or potassium tert-butoxide, alkali metal hydrides, such as sodium hydride
or potassium hydride, amides, such as lithium bis(trimethylsilyl)amide or
potassium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA),
organic amines, such as triethylamine, N-methylmorpholine,
N-methylpiperidine, N,N-diisopropylethylamine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or
4-N,N-dimethylaminopyridine, or phosphazene bases ("Schwesinger bases"),
such as, for example, P1-t-Bu, P2-t-Bu or P4-t-Bu. Preference is given to
using potassium carbonate, caesium carbonate, sodium hydride,
triethylamine, N,N-diisopropylethylamine or lithium
bis(trimethylsilyl)amide; particular preference is given to sodium
hydride and lithium bis(trimethylsilyl)amide. The base is generally
employed in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to
3 mol, based on 1 mol of the compound (XII-A).

[0190] The process step (XII-A)+(XIII)→(XII-B) is generally carried
out in a temperature range of from -78° C. to +100° C.,
preferably at from -78° C. to +80° C., particularly
preferably at from -78° C. to +25° C. The reaction can be
carried out at atmospheric, elevated or reduced pressure (for example
from 0.5 to 5 bar); in general, the process is carried out at atmospheric
pressure.

[0191] The reduction of the nitro compound (XII-A) or (XII-B) to the
aniline derivative (II) is carried out in accordance with standard
methods by catalytic hydrogenation in the presence of a customary
palladium or platinum catalyst; preference is given to using palladium on
activated carbon. The hydrogenation can take place at atmospheric or at
elevated hydrogen pressure; in general, it is carried out at atmospheric
pressure. The reaction is preferably carried out at room temperature in
alcoholic solvents such as methanol or ethanol, if appropriate with the
use of inert cosolvents such as, for example, tetrahydrofuran or ethyl
acetate.

[0192] According to one process variant, if the radical R1 in formula
(I) represents cyano, instead of the compound (X) it is also possible to
use an acetoacetic ester of the formula (XIV)

##STR00028##

in which T represents (C1-C4)-alkyl or allyl, in the
condensation reaction with the compounds (IX) and (XI); the resulting
product of the formula (XV)

##STR00029##

in which R3 and T have the meanings given above, can then, by
standard methods via ester cleavage to give the carboxylic acid of the
formula (XVI)

##STR00030##

in which R3 has the meaning given above, subsequent conversion into
the primary carboxamide of the formula (XVII)

##STR00031##

in which R3 has the meaning given above, and subsequent dehydration
of the amide grouping be converted into the 5-cyanodihydropyrimidinone of
the formula (XII-A) [R1═CN] (cf. Reaction Scheme 1 below).

[0193] The compounds of the formula (V) can be prepared in an analogous
manner by initially reacting 4-cyano-2-fluorobenzaldehyde of the formula
(XVIII)

##STR00032##

with a thiol of the formula (XIX)

RZ3--SH (XIX),

in which RZ3 has the meaning given above, in the presence of a base
to give a 2-sulfanyl-substituted benzaldehyde of the formula (XX)

##STR00033##

in which RZ3 has the meaning given above, and then reacting this
compound further in exchange for the compound (IX) according to the
reaction sequence (IX)+(X)+(XI)→(XII-A)→(XII-B) or
(IX)+(XIV)+(XI)→(XV)→(XVI)→(XVII)→(XII-A)
described above (cf. Reaction Scheme 2 below).

[0194] If expedient, further compounds of the formula (I) according to the
invention can also be prepared by transformations of functional groups of
individual substituents, in particular those listed under RZ1 and
RZ2, starting with other compounds of the formula (I) obtained by
the above process. These transformations are carried out according to
customary methods known to the person skilled in the art and include, for
example, reactions such as nucleophilic or electrophilic substitution
reactions, transition metal-mediated coupling reactions (for example
Suzuki, Heck or Hartwig-Buchwald reaction), oxidation, reduction,
hydrogenation, alkylation, acylation, amination, hydroxylation,
etherification, esterification, ester cleavage and ester hydrolysis,
formation of nitriles, carboxamides and carbamates, and also the
introduction and removal of temporary protective groups

[0195] Separation of the compounds according to the invention into the
corresponding enantiomers and/or diastereomers is possible, as expedient,
at the stage of the compounds (I-A), (I-B) and (I-C) or even at the stage
of the compounds (II), (V), (VI) or (VII) or else of the intermediates
(XII-A), (XII-B), (XV), (XVI) or (XVII) or their RZ3S-substituted
analogs, where these intermediates can then, in separated form, be
reacted further according to the process steps described above. Such a
separation of stereoisomers can be carried out by customary methods known
to the person skilled in the art; preference is given to chromatographic
methods, in particular to HPLC chromatography on a chiral phase.

[0196] The compounds of the formulae (IV), (VIII), (IX), (X), (XI),
(XIII), (XIV), (XVIII) and (XIX) are commercially available, known per se
from the literature or can be prepared by customary methods described in
the literature.

[0197] The processes described above can be illustrated in an exemplary
manner by the reaction schemes below:

##STR00034##

##STR00035##

##STR00036##

##STR00037##

[0198] The compounds according to the invention have useful
pharmacological properties and can be used for prevention and treatment
of disorders in humans and animals.

[0199] The compounds according to the invention are low-molecular-weight,
unreactive and selective inhibitors of human neutrophil elastase which,
surprisingly, effect a considerably stronger inhibition of this protease
than the compounds known from the prior art. In addition, the compounds
according to the invention unexpectedly have a low in vitro clearance
with respect to hepatocytes and thus have improved metabolic stability.
Moreover, some of the compounds according to the invention have good
solubility in aqueous systems which is advantageous with regard to their
general formulatibility and/or intravenous administrability.

[0200] Accordingly, the compounds according to the invention are
particularly suitable for the treatment and/or prevention of disorders
and pathological processes, in particular those where neutrophil elastase
(HNE) is involved in an inflammatory event and/or a tissue or vessel
remodeling.

[0205] The present invention furthermore provides the use of the compounds
according to the invention for the treatment and/or prevention of
disorders, in particular the disorders mentioned above.

[0206] The present invention furthermore provides the use of the compounds
according to the invention for preparing a medicament for the treatment
and/or prevention of disorders, in particular the disorders mentioned
above.

[0207] The present invention furthermore provides the use of the compounds
according to the invention in a method for the treatment and/or
prevention of disorders, in particular the disorders mentioned above.

[0208] The present invention furthermore provides a method for the
treatment and/or prevention of disorders, in particular the disorders
mentioned above, using an effective amount of at least one of the
compounds according to the invention.

[0209] The compounds according to the invention can be employed alone or,
if required, in combination with other active compounds. Accordingly, the
present invention furthermore provides medicaments comprising at least
one of the compounds according to the invention and one or more further
active compounds, in particular for the treatment and/or prevention of
the disorders mentioned above. Suitable active compounds for combinations
are, by way of example and preferably: [0210] compounds which inhibit
the signal transduction cascade, for example and preferably from the
group of the kinase inhibitors, in particular from the group of the
tyrosine kinase and/or serine/threonine kinase inhibitors; [0211]
compounds which inhibit the degradation and remodelling of the
extracellular matrix, for example and preferably inhibitors of matrix
metalloproteases (MMPs), in particular inhibitors of stromelysin,
collagenases, gelatinases and aggrecanases (here in particular of MMP-1,
MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase
(MMP-12); [0212] compounds which block the binding of serotonin to its
receptor, for example and preferably antagonists of the 5-HT2b
receptor; [0213] organic nitrates and NO donors, such as, for example,
sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide
dinitrate, molsidomine or SIN-1, and also inhaled NO; [0214]
NO-independent but hem-dependent stimulators of soluble guanylate
cyclase, such as, in particular, the compounds described in WO 00/06568,
WO 00/06569, WO 02/42301 and WO 03/095451; [0215] NO- and hem-independent
activators of soluble guanylate cyclase, such as, in particular, the
compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO
01/19780, WO 02/070462 and WO 02/070510; [0216] prostacycline analogs,
such as, by way of example and preferably, iloprost, beraprost,
treprostinil or epoprostenol; [0217] compounds which inhibit soluble
epoxide hydrolase (sEH), such as, for example, N,N'-dicyclohexylurea,
12-(3-adamantan-1-ylureido)dodecanoic acid or
1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea; [0218]
compounds which influence the energy metabolism of the heart, such as, by
way of example and preferably, etomoxir, dichloroacetate, ranolazine or
trimetazidine; [0219] compounds which inhibit the degradation of cyclic
guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate
(cAMP), such as, for example, inhibitors of phosphodiesterases (PDE) 1,
2, 3, 4 and/or 5, in particular PDE 5 inhibitors, such as sildenafil,
vardenafil and tadalafil; [0220] agents having antithrombotic action, by
way of example and preferably from the group of the platelet aggregation
inhibitors, of anticoagulants or of profibrinolytic substances; [0221]
active compounds which lower blood pressure, by way of example and
preferably from the group of the calcium antagonists, angiotensin AII
antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin
antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor
blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors
and diuretics; [0222] agents having a bronchodilatory effect, by way of
example and preferably from the group of the beta-adrenergic receptor
agonists, such as, in particular, albuterol, isoproterenol,
metaproterenol, terbutalin, formoterol or salmeterol, or from the group
of the anticholinergics, such as, in particular, ipratropium bromide;
[0223] agents having antiinflammatory action, by way of example and
preferably from the group of the glucocorticoids, such as, in particular,
prednisone, prednisolone, methylprednisolone, triamcinolone,
dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or
fluticasone; and/or [0224] active compounds which alter lipid metabolism,
for example and preferably from the group of the thyroid receptor
agonists, cholesterol synthesis inhibitors, such as, by way of example
and preferably, HMG-CoA reductase inhibitors or squalene synthesis
inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,
PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption
inhibitors, lipase inhibitors, polymeric bile adsorbents, bile acid
reabsorption inhibitors and lipoprotein(a) antagonists.

[0225] In a preferred embodiment of the invention, the compounds according
to the invention are employed in combination with a kinase inhibitor such
as by way of example and preferably bortezomib, canertinib, erlotinib,
gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib,
pelitinib, semaxanib, sorafenib, sunitinib, tandutinib, tipifarnib,
vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

[0226] In a preferred embodiment of the invention, the compounds according
to the invention are employed in combination with a serotonin receptor
antagonist such as, by way of example and preferably, PRX-08066.

[0227] Agents having an antithrombotic effect preferably mean compounds
from the group of platelet aggregation inhibitors, of anticoagulants or
of profibrinolytic substances.

[0228] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a platelet
aggregation inhibitor such as by way of example and preferably aspirin,
clopidogrel, ticlopidine or dipyridamole.

[0229] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a thrombin
inhibitor such as by way of example and preferably ximelagatran,
melagatran, bivalirudin or clexane.

[0230] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a GPIIb/IIIa
antagonist such as by way of example and preferably tirofiban or
abciximab.

[0231] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a factor Xa
inhibitor such as by way of example and preferably rivaroxaban, DU-176b,
fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150,
KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803,
SSR-126512 or SSR-128428.

[0232] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with heparin or a low
molecular weight (LMW) heparin derivative.

[0233] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a vitamin K
antagonist such as by way of example and preferably coumarin.

[0235] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a calcium
antagonist such as by way of example and preferably nifedipine,
amlodipine, verapamil or diltiazem.

[0236] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an alpha-1 receptor
blocker such as by way of example and preferably prazosin.

[0237] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a beta-receptor
blocker such as by way of example and preferably propranolol, atenolol,
timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,
metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,
betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,
carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0238] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an angiotensin AII
antagonist such as by way of example and preferably losartan,
candesartan, valsartan, telmisartan or embusartan.

[0239] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an ACE inhibitor
such as by way of example and preferably enalapril, captopril,
lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or
trandopril.

[0240] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an endothelin
antagonist such as by way of example and preferably bosentan, darusentan,
ambrisentan or sitaxsentan.

[0241] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a renin inhibitor
such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

[0242] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a mineralocorticoid
receptor antagonist such as by way of example and preferably
spironolactone or eplerenone.

[0243] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a Rho kinase
inhibitor such as by way of example and preferably fasudil, Y-27632,
SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A
or BA-1049.

[0244] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a diuretic such as
by way of example and preferably furosemide.

[0246] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a CETP inhibitor
such as by way of example and preferably torcetrapib (CP-529 414),
JJT-705 or CETP vaccine (Avant).

[0247] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a thyroid receptor
agonist such as by way of example and preferably D-thyroxine,
3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0248] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an HMG-CoA
reductase inhibitor from the class of statins such as by way of example
and preferably lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, rosuvastatin or pitavastatin.

[0249] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a squalene
synthesis inhibitor such as by way of example and preferably BMS-188494
or TAK-475.

[0250] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an ACAT inhibitor
such as by way of example and preferably avasimibe, melinamide,
pactimibe, eflucimibe or SMP-797.

[0251] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an MTP inhibitor
such as by way of example and preferably implitapide, BMS-201038,
R-103757 or JTT-130.

[0252] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a PPAR-gamma
agonist such as by way of example and preferably pioglitazone or
rosiglitazone.

[0253] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a PPAR-delta
agonist such as by way of example and preferably GW-501516 or BAY
68-5042.

[0254] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a cholesterol
absorption inhibitor such as by way of example and preferably ezetimibe,
tiqueside or pamaqueside.

[0255] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a lipase inhibitor
such as by way of example and preferably orlistat.

[0256] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a polymeric bile
acid adsorbent such as by way of example and preferably cholestyramine,
colestipol, colesolvam, CholestaGel or colestimide.

[0257] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a bile acid
reabsorption inhibitor such as by way of example and preferably
ASBT(=IBAT) inhibitors such as, for example, AZD-7806, S-8921, AK-105,
BARI-1741, SC-435 or SC-635.

[0258] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a lipoprotein(a)
antagonist such as by way of example and preferably gemcabene calcium
(CI-1027) or nicotinic acid.

[0259] The present invention further provides medicaments comprising at
least one compound according to the invention, usually in combination
with one or more inert, non-toxic, pharmaceutically suitable excipients,
and their use for the purposes mentioned above.

[0260] The compounds according to the invention may have systemic and/or
local effects. For this purpose, they can be administered in a suitable
way such as, for example, by the oral, parenteral, pulmonary, nasal,
sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or
otic route or as implant or stent.

[0261] The compounds according to the invention can be administered in
administration forms suitable for these administration routes.

[0262] Suitable for oral administration are administration forms which
function according to the prior art and deliver the compounds according
to the invention rapidly and/or in a modified manner, and which contain
the compounds of the invention in crystalline and/or amorphized and/or
dissolved form, such as, for example, tablets (uncoated and coated
tablets, for example having coatings which are resistant to gastric juice
or are insoluble or dissolve with a delay and control the release of the
compound of the invention), tablets which disintegrate rapidly in the
mouth, or films/wafers, films/lyophilizates, capsules (for example hard
or soft gelatin capsules), sugar-coated tablets, granules, pellets,
powders, emulsions, suspensions, aerosols or solutions.

[0263] Parenteral administration can take place with avoidance of an
absorption step (e.g. intravenous, intraarterial, intracardiac,
intraspinal or intralumbar) or with inclusion of an absorption (e.g.
inhalative, intramuscular, subcutaneous, intracutaneous, percutaneous, or
intraperitoneal). Administration forms suitable for parenteral
administration are, inter alia, preparations for injection and infusion
in the form of solutions, suspensions, emulsions, lyophilizates or
sterile powders.

[0267] It has generally proved to be advantageous on parenteral
administration to administer amounts of about 0.001 to 1 mg/kg,
preferably about 0.01 to 0.5 mg/kg of body weight to achieve effective
results. On oral administration, the dosage is about 0.01 to 100 mg/kg,
preferably about 0.01 to 20 mg/kg, and very particularly preferably 0.1
to 10 mg/kg of body weight.

[0268] It may nevertheless be necessary where appropriate to deviate from
the stated amounts, in particular as a function of body weight,
administration route, individual response to the active compound, type of
preparation and time or interval over which administration takes place.
Thus, in some cases it may be sufficient to make do with less than the
aforementioned minimum amount, whereas in other cases the upper limit
mentioned must be exceeded. Where relatively large amounts are
administered, it may be advisable to distribute these in a plurality of
single doses over the day.

[0269] The following exemplary embodiments illustrate the invention. The
invention is not restricted to the examples.

[0270] The percentage data in the following tests and examples are, unless
indicated otherwise, percentages by weight; parts are parts by weight.
Solvent ratios, dilution ratios and concentration data of liquid/liquid
solutions are in each case, unless indicated otherwise, based on the
volume.

[0326] The reaction was carried out under argon. At RT, allyl acetoacetate
(5.94 g, 41.5 mmol; 1.0 eq.) was initially charged in THF (117 ml).
4-Cyano-2-nitrobenzaldehyde (10.45 g, 70% pure, 41.5 mmol; 1.0 eq.),
1-[3-(trifluoromethyl)phenyl]urea (8.48 g, 41.5 mmol) and triethyl
phosphate (17.7 g) were then added. The mixture was stirred under reflux
for 16 h. For work-up, ice-water was initially added, and the mixture was
then taken up in ethyl acetate (400 ml). The organic phase was dried over
solid sodium sulfate, filtered and concentrated under reduced pressure.
The crude product was recrystallized from hot water/isopropanol (2:1,
˜400 ml). The solid obtained was stirred in diethyl ether (60 ml),
once more filtered off with suction, washed with a little diethyl ether
and dried under high vacuum. The title compound was obtained as a solid
(16.63 g, 82% of theory).

[0330] The reaction was carried out under argon. (rac)-Allyl
4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,-
2,3,4-tetrahydropyrimidine-5-carboxylate (15.0 g, 30.8 mmol) and
morpholine (1.5 eq., 4.03 g, 46.3 mmol) were initially charged in dry THF
(300 ml) at RT. The reaction mixture was degassed repeatedly (evacuation
followed by venting with argon). Under protective gas,
tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 1.78 g, 1.54 mmol)
was added and the reaction mixture was stirred at RT for 2 h (monitored
by HPLC). The mixture was then concentrated and the residue was taken up
in ethyl acetate (700 ml). The organic phase was washed with 0.5 N
hydrochloric acid (500 ml) and with saturated sodium chloride solution
(300 ml), dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was recrystallized from ethyl acetate
and dried under high vacuum. The title compound was obtained as a solid
(12.87 g, 93% of theory).

[0339] The reaction was carried out under argon.
(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)pheny-
l]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.0 g, 10.1 mmol; 90% pure)
was initially charged in dry THF (135 ml),
methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 3.85
g, 16.17 mmol; 1.6 eq.) was added and the mixture was then stirred at RT
for 2 h. Ethyl acetate (300 ml) was then added to the reaction mixture.
The organic phase was washed twice with water and once with saturated
sodium chloride solution, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was recrystallized
from cyclohexane/ethyl acetate. The crystals obtained were dried under
high vacuum. The title compound was obtained as a solid (2.8 g, 65% of
theory).

[0346] Under argon,
(4R)-4-(4-cyano-2-nitrophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)p-
henyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (6.0 g, 11.3 mmol) was
dissolved in methanol (420 ml). 10% Palladium on activated carbon (5.5 g)
was then added, and the mixture was hydrogenated at RT and atmospheric
pressure for 5.5 h (strictly monitored by HPLC). The reaction mixture was
then filtered through kieselguhr and the filter residue was washed with
methanol (1000 ml). The filtrate was concentrated and the crude product
was subjected to flash chromatography on silica gel (mobile phase: ethyl
acetate/cyclohexane 2:1). The title compound was obtained as a solid
(2.28 g, 40% of theory).

[0349] Under argon,
(4R)-4-(2-amino-4-cyanophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)p-
henyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (2.1 g, 5.1 mmol) was
initially charged in a 2:1:1 mixture of acetic acid/conc. hydrochloric
acid/water (50 ml in total) at -10° C. A solution of sodium
nitrite (371 mg, 5.38 mmol) in water (2 ml) was slowly added dropwise,
and the mixture was stirred at -10° C. to -5° C. for 40
min. This solution was then added to 45 ml of a suspension, pre-cooled to
-10° C. and saturated with sulfur dioxide, of copper(I) chloride
(101.4 mg, 1.0 mmol) in glacial acetic acid (44 ml). The mixture was
stirred at 0° C. for about 30 min and then at +15° C. for 1
h (reaction monitored by HPLC and LC-MS). The reaction mixture was then
once more cooled to 0° C. and then pipetted into about 300 ml of
ice-cold water. The precipitate was filtered off and taken up in ethyl
acetate (150 ml). The solution was washed twice with saturated sodium
chloride solution, dried over sodium sulfate, filtered and concentrated
under reduced pressure. The title compound was obtained as a solid (2.13
g, 77% of theory, 92% pure) which was used without further purification
for subsequent reactions.

[0353] Under argon,
(4R)-4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)pheny-
l]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (39.5 g, 92.4 mmol) was
dissolved in ethanol (1975 ml). 10% Palladium on activated carbon (19.8
g) was then added, and the mixture was hydrogenated at RT and atmospheric
pressure for 2 h (strictly monitored by TLC). The reaction mixture was
then filtered through kieselguhr. The filtrate was concentrated and the
crude product obtained was subjected to flash chromatography on silica
gel (mobile phase: ethyl acetate/cyclohexane 2:1). The title compound was
obtained as a solid (25.5 g, 68% of theory).

[0356] Under argon,
(4R)-4-(2-amino-4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)pheny-
l]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (3.0 g, 7.55 mmol) was
initially charged in a 2:1:1 mixture of acetic acid/conc. hydrochloric
acid/water (50 ml in total) at -10° C. A solution of sodium
nitrite (547 mg, 7.93 mmol) in water (6 ml) was added, and the mixture
was stirred at -10° C. for 15 min. This solution was then added to
a suspension, pre-cooled to -10° C. and saturated with sulfur
dioxide, of copper(I) chloride (75 mg, 755 μmol; 0.1 eq.) in glacial
acetic acid (60 ml). The reaction was stirred at -10° C. (internal
temperature) for 60 min and then slowly, over a period of 3 h, warmed to
+15° C. (reaction monitored by HPLC and LC-MS). The reaction
mixture was then once more cooled to 0° C., and then pipetted into
about 300 ml of ice-cold water. The aqueous phase was extracted
repeatedly with MTBE. The combined organic phases were washed twice with
saturated sodium chloride solution, dried over sodium sulfate, filtered
and concentrated under reduced pressure. The title compound was obtained
as a solid (1.67 g, 73% pure according to LCMS, 32% of theory) and used
without further purification for subsequent reactions.

[0359] The reaction was carried out under argon.
3-Fluoro-4-methylbenzonitrile (121 g, 895 mmol) and N,N-dimethylformamide
dimethylacetal (245 g, 2.06 mol) were dissolved in DMF (1.8 liters) and
stirred under reflux overnight. The content of the flask was then poured
into water (2 liters), the mixture was extracted twice with ethyl acetate
and the combined organic phases were washed with saturated sodium
chloride solution. The organic phase was concentrated and the residue was
redissolved in THF/water (1:1, 2.7 liters). Sodium periodate (503 g, 2.35
mol) was added, and the mixture was stirred at room temperature for one
hour. The precipitate was then removed and the filtrate was recovered and
extracted repeatedly with ethyl acetate. The combined organic phases were
washed once with saturated sodium bicarbonate solution and once with
saturated sodium chloride solution, dried and concentrated to give an
oil. This oil was purified by column chromatography on silica gel (mobile
phase: petroleum ether/dichloromethane 6:4, then 4:6, finally pure
dichloromethane). The product fractions were concentrated. This gave 28.0
g (20% of theory) of the target compound as a white crystalline solid.

[0363] 3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol) was dissolved in
DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5 mmol) was added
with ice-bath cooling. The mixture was stirred for 45 min and then
diluted with water (100 ml). The resulting precipitated product was
filtered off with suction, washed with water and dried under reduced
pressure. This gave 1.36 g (51% of theory) of the target compound as a
yellow crystalline solid.

[0366] The reaction was carried out under argon. Triethyl phosphate (1.46
g, 8.04 mmol) and phosphorus pentoxide (761 mg, 5.36 mmol) were stirred
at 50° C. overnight. The mixture was then diluted with MTBE (27
ml), and 4-formyl-3-(methylsulfanyl)benzonitrile (1.18 g, 6.70 mmol),
1-[3-(trifluoromethyl)phenyl]urea (1.37 g, 6.70 mmol) and allyl
acetoacetate (1.43 g, 10.1 mmol) were added. The mixture was stirred
under reflux overnight. For work-up, the solvent was removed under
reduced pressure and the residue was suspended in diethyl ether and then
filtered off with suction. This gave 978 mg (19% of theory) of the title
compound.

[0369] Allyl(rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-
-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (750
mg, 1.54 mmol) was dissolved in THF (10 ml), and morpholine (201 mg,
2.308 mmol) was added. The reaction solution was saturated with argon
(argon was passed through the solution for 30 min).
Tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was then
added, and the mixture was stirred at RT overnight. Since HPLC showed
little conversion, more tetrakis(triphenylphosphine)palladium(0) (7.47
mg, 0.006 mmol) was added and the mixture was stirred at RT for a further
3 h. The content of the flask was then filtered through kieselguhr and
the residue was washed with THF. The filtrate was concentrated under
reduced pressure and the residue was recrystallized from diethyl ether
(15 ml). The crystals were filtered off with suction and dried under high
vacuum. This gave 663 mg (96% of theory) of the target compound.

[0378] The reaction was carried out under argon.
(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluorom-
ethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (240 mg,
0.536 mmol) was dissolved in THF (5 ml), and PyBOP (419 mg, 0.805 mmol)
and triethylamine (380 mg, 3.76 mmol) were added. After brief stirring
the mixture was cooled to 0° C., and ammonium chloride (143 mg,
2.68 mmol) was added. The reaction mixture was stirred at RT overnight
and the content of the flask was then added to 1 N hydrochloric acid. The
mixture was extracted twice with ethyl acetate, and the combined organic
phases were washed with 1 N hydrochloric acid and with saturated sodium
chloride solution, dried and concentrated. The residue was purified by
preparative HPLC. This gave 161 mg (67% of theory) of the title compound.

[0381] The reaction was carried out under argon.
(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluorom-
ethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (95.0 mg, 0.213
mmol) was dissolved in THF (4 ml), and
methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 101
mg, 0.426 mmol) was added. After 30 min of stirring at room temperature,
HPLC showed complete conversion. The mixture was diluted with ethyl
acetate (4 ml), and water (1 ml) was added. The mixture was then applied
to a Merck Extrelut® NT3 column and the filtrate was purified by
preparative HPLC. Concentration of the product fractions gave 96.0 mg
(quant.) of the title compound.

[0386] (4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trif-
luoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (55 mg,
0.13 mmol) was dissolved in ethanol (5.5 ml), and methyltrioxorhenium
(3.20 mg, 0.013 mmol) and hydrogen peroxide (16.0 mg, 0.14 mmol) were
added. The reaction mixture was stirred at RT for 60 min and then
concentrated under reduced pressure, and the residue was purified by
preparative HPLC. This gave 27 mg (47% of theory) of the target compound
as a diastereomer mixture.

[0388] (4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trif-
luoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (2.00 g,
4.67 mmol) was initially charged in methanol/water (4.4:1, ˜40 ml),
sodium periodate (1.90 g, 8.87 mmol; 1.9 eq.) was added and the mixture
was stirred at 30° C. for 16 h. More sodium periodate (0.45 g,
2.10 mmol; 0.45 eq.) was then added, and the reaction was stirred at
50° C. for a further 4 h (monitored by HPLC). The reaction mixture
was then added to saturated aqueous sodium bicarbonate solution
(˜200 ml) and extracted with ethyl acetate (4×50 ml). The
combined organic phases were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was subjected to
flash chromatography on silica gel (gradient cyclohexane→ethyl
acetate). The target compound was obtained as a diastereomer mixture in
the form of a colorless solid (2.18 g, quant.).

[0392] The reaction was carried out under argon. The diastereomer mixture
of (RS,
4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluorome-
thyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile and (SS,
4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluorome-
thyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (535 mg, 1.2
mmol) was initially charged in absolute THF (12 ml), and a 1 M solution
of lithium hexamethyldisilazide (LiHMDS) in THF (1.45 ml; 1.2 eq.) was
added at -78° C. After 20 min of stirring at -78° C.,
iodomethane (854 mg; 5 eq.) was added and the mixture was stirred for 16
h with gradual warming from -78° C. to RT. The reaction mixture
was then concentrated under reduced pressure, saturated ammonium chloride
solution (50 ml) was added and the mixture was then extracted with ethyl
acetate (3×30 ml). The combined organic phases were dried over
solid sodium sulfate, filtered and concentrated under reduced pressure
and the residue was purified by preparative HPLC (column: Gromsil C-18 10
μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10).
This gave the title compound as a solid (488 mg, 88% of theory).

[0481] The reaction was carried out under argon. The diastereomer mixture
from Example 23A (485 mg, 873 μmol) was initially charged in an
acetonitrile/methanol mixture (10:1, 44 ml). At 0° C., solid
potassium carbonate (60.3 mg, 437 μmol; 0.5 eq.) was added and the
reaction was stirred for 15 min. The mixture was then neutralized with
trifluoroacetic acid (49.8 mg, 437 μmol; 0.5 eq.) and concentrated
under reduced pressure and the residue was taken up in ethyl acetate (50
ml). The organic phase was washed with saturated aqueous sodium chloride
solution (2×15 ml), dried over sodium sulfate, filtered and
concentrated under reduced pressure. The title compound was isolated as a
solid (400 mg, quant.).

[0510] The potency of the compounds of the invention is ascertained in an
in vitro inhibition assay. The HNE-mediated amidolytic cleavage of a
suitable peptide substrate leads in this connection to an increase in the
fluorescent light. The signal intensity of the fluorescent light is
directly proportional to the enzyme activity. The effective concentration
of a test compound at which half the enzyme is inhibited (50% signal
intensity of the fluorescent light) is indicated as IC50.

Procedure:

[0511] Enzyme (80 pM HNE; from Serva, Heidelberg) and substrate (20 μM
MeOSuc-Ala-Ala-Pro-Val-AMC; from Bachem, Weil am Rhein) are incubated in
an assay volume of in total 50 μl of assay buffer (0.1 M HEPES pH 7.4,
0.5 M NaCl, 0.1% w/v BSA, 1% v/v DMSO) in a 384-well microtiter plate in
the presence and absence of the test substance at 37° C. for 2
hours. The intensity of the fluorescent light from the assay mixtures is
measured (Ex. 380 nm, Em. 460 nm). The IC50 values are determined by
plotting the intensity of the fluorescent light against the active
compound concentration.

[0512] Representative IC50 values for the compounds of the invention
(at an HNE concentration of 80 pM) are shown in Table A below:

[0513] The monocrotaline-induced pulmonary hypertension in rats is a
widely used animal model of pulmonary arterial hypertension. The
pyrrolizidine alkaloid monocrotaline is metabolized after subcutaneous
injection to the toxic monocrotalinepyrrole in the liver and leads within
a few days to endothelial damage in the pulmonary circulation, followed
by a remodeling of the small pulmonary arteries (media hypertrophy, de
novo muscularization). A single subcutaneous injection is sufficient to
induce pronounced pulmonary hypertension in rats within 4 weeks [Cowan et
al., Nature Med. 6, 698-702 (2000)].

[0514] Male Sprague-Dawley rats are used for the model. On day 0, the
animals receive a subcutaneous injection of 60 mg/kg monocrotaline.
Treatment of the animals begins no earlier than 14 days after the
monocrotaline injection and extends over a period of at least 14 days. At
the end of the study, the animals undergo hemodynamic investigations, and
the arterial and central venous oxygen saturation are determined. For the
hemodynamic measurement, the rats are initially anesthetized with
pentobarbital (60 mg/kg). The animals are then tracheotomized and
artificially ventilated (rate: 60 breaths/min; inspiration to expiration
ratio: 50:50; positive end-expiratory pressure: 1 cm H2O; tidal
volume: 10 ml/kg of body weight; FIO2: 0.5). The anesthesia is
maintained by isoflurane inhalation anesthesia. The systemic blood
pressure is determined in the left carotid artery using a Millar microtip
catheter. A polyethylene catheter is advanced through the right jugular
vein into the right ventricle to determine the right ventricular
pressure. The cardiac output is determined by thermodilution. Following
the hemodynamics, the heart is removed and the ratio of right to left
ventricle including septum is determined. In addition, plasma samples are
obtained to determine biomarkers (for example proBNP) and plasma
substance levels.

[0516] Elastase-induced pulmonary emphysema in mice, rats or hamsters is a
widely used animal model of pulmonary emphysema [Sawada et al., Exp. Lung
Res. 33, 277-288 (2007)]. The animals receive an orotracheal instillation
of porcine pancreas elastase. The treatment of the animals starts at the
day of the instillation of the porcine pancreas elastase and extends over
a period of 3 weeks. At the end of the study, the pulmonary compliance is
determined, and an alveolar morphometry is carried out.

B-5. CYP Inhibition Assay

[0517] The ability of substances to be able to inhibit CYP1A2, CYP2C9,
CYP2D6 and CYP3A4 in humans is investigated with pooled human liver
microsomes as enzyme source in the presence of standard substrates (see
below) which form CYP-specific metabolites. The inhibitory effects are
investigated with six different concentrations of the test compounds
[2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μM], compared with the extent
of the CYP-specific metabolite formation of the standard substrates in
the absence of the test compounds, and the corresponding IC50 values
are calculated. A standard inhibitor which specifically inhibits a single
CYP isoform is always included in the incubation in order to make the
results comparable between different series.

Procedure:

[0518] Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan
or midazolam with human liver microsomes in the presence of in each case
six different concentrations of a test compound (as potential inhibitor)
is carried out on a work station (Tecan, Genesis, Crailsheim, Germany).
Standard incubation mixtures comprise 1.3 mM NADP, 3.3 mM
MgCl2×6 H2O, 3.3 mM glucose 6-phosphate, glucose
6-phosphate dehydrogenase (0.4 U/ml) and 100 mM phosphate buffer (pH 7.4)
in a total volume of 200 μl. Test compounds are preferably dissolved
in acetonitrile. 96-well plates are incubated with pooled human liver
microsomes at 37° C. for a defined time. The reactions are stopped
by adding 100 μl of acetonitrile in which a suitable internal standard
is always present. Precipitated proteins are removed by centrifugation,
and the supernatants are combined and analyzed by LC-MS/MS.

B-6. Hepatocyte Assay to Determine the Metabolic Stability

[0519] The metabolic stability of test compounds in the presence of
hepatocytes is determined by incubating the compounds with low
concentrations (preferably below or around 1 μM) and with low cell
counts (preferably 1*106 cells/ml) in order to ensure as far as
possible linear kinetic conditions in the experiment. Seven samples of
the incubation solution are taken in a fixed time pattern for the LD-MS
analysis in order to determine the half-life (i.e. the degradation) of
the compound in each case. Various clearance parameters (CL) and
Fmax values are calculated from this half-life (see below).

[0520] The Cl and Fmax values represent a measure of the phase 1 and
phase 2 metabolism of the compounds in the hepatocytes. In order to
minimize the influence of the organic solvent on the enzymes in the
incubation mixtures, this concentration is generally limited to 1%
(acetonitrile) or 0.1% (DMSO).

[0521] A cell count for hepatocytes in the liver of 1.1*108 cells/g
of liver is used for calculation for all species and breeds. CL
parameters calculated on the basis of half-lives extending substantially
beyond the incubation time (normally 90 minutes) can be regarded only as
rough guidelines.

[0538] At least 4 mg of the test substance are weighed accurately into a
wide-necked 10 mm screw V vial (from Glastechnik Grafenroda GmbH, Art.
No. 8004-WM-HN15μ) with fitting screw cap and septum, in a pipetting
robot DMSO is added to a concentration of 50 mg/ml and the mixture is
shaken for 10 minutes.

Preparation of the Calibration Solutions:

[0539] Preparation of the Starting Solution for Calibration Solutions
(Stock Solution): with the Aid of a pipetting robot, 10 μl of the
original solution are transferred into a microtiter plate and made up
with DMSO to a concentration of 600 μg/ml. The sample is shaken until
everything has gone into solution.

[0540] Calibration solution 1 (20 μg/ml): 1000 μl of DMSO are added
to 34.4 μl of the stock solution, and the mixture is homogenized.

[0542] Sample solution for solubilities of up to 5 g/liter in PBS buffer
pH 6.5: 10 μl of the original solution are transferred into a
microtiter plate, and 1000 μl of PBS buffer pH 6.5 are added.

[0543] Sample solution for solubilities of up to 5 g/liter in PEG/water
(70:30): 10 μl of the original solution are transferred into a
microtiter plate, and 1000 μl of PEG/water (70:30) are added.

[0544] Sample solution for solubilities of up to 5 g/liter in PEG/PBS
buffer pH 6.5 (20:80): 10 μl of the original solution are transferred
into a microtiter plate, and 1000 μl of PEG/PBS buffer pH 6.5 (20:80)
are added.

Practice:

[0545] The sample solutions prepared in this manner are shaken at 1400 rpm
in a temperature-adjustable shaker (for example Eppendorf Thermomixer
comfort Art. No. 5355 000.011 with interchangeable block Art. No.
5362.000.019) at 20° C. for 24 hours. In each case 180 μl are
taken from these solutions and transferred into Beckman Polyallomer
Centrifuge Tubes (Art. No. 343621). These solutions are centrifuged at
about 223 000×g for one hour (for example Beckman Optima L-90K
Ultracentrifuge with Type 42.2 Ti Rotor at 42 000 rpm). From each of the
sample solutions, 100 μl of the supernatant are removed and diluted
1:5 and 1:100 with DMSO. From each dilution, a sample is transferred into
a vessel suitable for HPLC analysis.

[0553] The mixture of compound of the invention, lactose and starch is
granulated with a 5% strength solution (m/m) of the PVP in water. The
granules are mixed with the magnesium stearate for 5 minutes after
drying. This mixture is compressed with a conventional tablet press (see
above for format of the tablet). A guideline compressive force for the
compression is 15 kN.

Suspension which can be Administered Orally:

Composition:

[0554] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%),
400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99
g of water.

[0555] 10 ml of oral suspension correspond to a single dose of 100 mg of
the compound of the invention.

Production:

[0556] The Rhodigel is suspended in ethanol, and the compound of the
invention is added to the suspension. The water is added while stirring.
The mixture is stirred for about 6 h until the swelling of the Rhodigel
is complete.

Solution which can be Administered Orally:

Composition:

[0557] 500 mg of the compound of the invention, 2.5 g of polysorbate and
97 g of polyethylene glycol 400.20 g of oral solution correspond to a
single dose of 100 mg of the compound according to the invention.

Production:

[0558] The compound of the invention is suspended in the mixture of
polyethylene glycol and polysorbate with stirring. The stirring process
is continued until the compound according to the invention has completely
dissolved.

i.v. Solution:

[0559] The compound of the invention is dissolved in a concentration below
the saturation solubility in a physiologically tolerated solvent (e.g.
isotonic saline solution, 5% glucose solution and/or 30% PEG 400
solution). The solution is sterilized by filtration and used to fill
sterile and pyrogen-free injection containers.

Patent applications by Dagmar Karthaus, Solingen DE

Patent applications by Daniel Meibom, Leverkusen DE

Patent applications by Dirk Schneider, Wuppertal DE

Patent applications by Franz Von Nussbaum, Dusseldorf DE

Patent applications by Klemens Lustig, Wuppertal DE

Patent applications by Martina Delbeck, Essen DE

Patent applications by Volkhart Min-Jian Li, Velbert DE

Patent applications by BAYER PHARMA AKTIENGESELLSCHAFT

Patent applications in class With additional active ingredient

Patent applications in all subclasses With additional active ingredient